A comprehensive screen for TWIST mutations in patients with craniosynostosis identifies a new microdeletion syndrome of chromosome band 7p21.1.

Mutations in the coding region of the TWIST gene (encoding a basic helix-loop-helix transcription factor) have been identified in some cases of Saethre-Chotzen syndrome. Haploinsufficiency appears to be the pathogenic mechanism involved. To investigate the possibility that complete deletions of the TWIST gene also contribute to this disorder, we have developed a comprehensive strategy to screen for coding-region mutations and for complete gene deletions. Heterozygous TWIST mutations were identified in 8 of 10 patients with Saethre-Chotzen syndrome and in 2 of 43 craniosynostosis patients with no clear diagnosis. In addition to six coding-region mutations, our strategy revealed four complete TWIST deletions, only one of which associated with a translocation was suspected on the basis of conventional cytogenetic analysis. This case and two interstitial deletions were detectable by analysis of polymorphic microsatellite loci, including a novel (CA)n locus 7.9 kb away from TWIST, combined with FISH; these deletions ranged in size from 3.5 Mb to >11.6 Mb. The remaining, much smaller deletion was detected by Southern blot analysis and removed 2,924 bp, with a 2-bp orphan sequence at the breakpoint. Significant learning difficulties were present in the three patients with megabase-sized deletions, which suggests that haploinsufficiency of genes neighboring TWIST contributes to developmental delay. Our results identify a new microdeletion disorder that maps to chromosome band 7p21.1 and that causes a significant proportion of Saethre-Chotzen syndrome.

Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis.

BACKGROUND: The C749G (Pro250Arg) mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) has been found in patients with various types of craniosynostosis. We aimed to find out the proportion of cases of apparently non-syndromic coronal craniosynostosis attributable to this mutation. METHODS: We studied 26 patients with coronal craniosynostosis but no syndromic diagnosis, who were referred to a supra-regional specialist centre. Genomic DNA was analysed by PCR and restriction-enzyme digestion to identify the C749G mutation in FGFR3. Family members of patients found to have the mutation were also tested. FINDINGS: Eight (31%) of the 26 probands were heterozygous for the C749G mutation. In two cases, the mutation showed autosomal dominant transmission with evidence of variable expressivity; the remaining six cases were sporadic. We demonstrated in six families that the mutation had arisen de novo from clinically unaffected parents. INTERPRETATION: The C749G mutation in FGFR3 is a frequent cause of apparently non-syndromic coronal craniosynostosis. Our finding will aid genetic counselling and prenatal diagnosis. The mutation rate at this nucleotide is one of the highest described in the human genome.

Craniofrontonasal dysplasia.

A series of 10 patients with craniofrontonasal dysplasia presenting to the Oxford Craniofacial Unit since 1983 is presented. In addition to the well-described combination of coronal synostosis and frontonasal dysplasia, 9 patients had very characteristic dry, curly or frizzy hair. All the patients were female. Recognition of the syndrome is important for genetic counselling, although the precise mode of genetic transmission is unclear with females predominating and males being less severely affected. Surgical correction was in two stages: early frontal advancement followed by correction of hypertelorism when the child became aware of the deformity. Four patients had their craniosynostosis treated in the Oxford Craniofacial Unit. Three patients had previously had frontal remodelling elsewhere. Nine patients had surgery for hypertelorism. The preferred technique for hypertelorism correction was facial bipartition. Following hypertelorism correction, the excess skin was allowed to redrape and subsequently dealt with by medial canthoplasties, thus avoiding a midline scar. Careful attention to the primary frontal advancement procedure is important to avoid complications following difficult dissection of the frontal bone flap at the time of hypertelorism correction.

Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.

Apert syndrome is a distinctive human malformation comprising craniosynostosis and severe syndactyly of the hands and feet. We have identified specific missense substitutions involving adjacent amino acids (Ser252Trp and Pro253Arg) in the linker between the second and third extracellular immunoglobulin (Ig) domains of fibroblast growth factor receptor 2 (FGFR2) in all 40 unrelated cases of Apert syndrome studied. Crouzon syndrome, characterized by craniosynostosis but normal limbs, was previously shown to result from allelic mutations of the third Ig domain of FGFR2. The contrasting effects of these mutations provide a genetic resource for dissecting the complex effects of signal transduction through FGFRs in cranial and limb morphogenesis.

The attachments of the temporomandibular joint meniscus in the human fetus.

The temporomandibular joints of human fetuses aged between 13 and 21 weeks have been examined by gross dissection and serial sections. An uninterrupted continuation of fibres has been observed from the superior head of the lateral pterygoid muscle to the malleus.