Disease relevance of Acrocephalosyndactylia

• This provides the first genetic evidence that signaling through KGFR causes syndactyly in Apert syndrome [1].
• These results together with our earlier observation that achondroplasia results from constitutive activation of the related receptor FGFR3, leads to the prediction that other malformation syndromes attributed to FGFRs, such as Pfeiffer syndrome and Thanatophoric dysplasia, also arise from constitutive receptor activation [2].
• Finally, since no TWIST mutations were detected in 40 cases of isolated coronal craniosynostosis, the present study suggests that TWIST mutations are specific to Saethre-Chotzen syndrome [3].
• Hydrocephalus occurred more frequently (five of 23 cases) in children with complex craniosynostosis syndromes, including Pfeiffer syndrome, Crouzon syndrome, and kleeblattschädel deformity [4].
• RESULTS: Phenotypic classification included Crouzon syndrome (n = 10), crouzonoid features with acanthosis nigricans (n = 3), Apert syndrome (n = 10), Pfeiffer syndrome (n = 4), and clinically unclassifiable bilateral coronal synostosis (n = 6) [5].

High impact information on Acrocephalosyndactylia

• Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities [6].
• Notably, multiple Twist1 mutations associated with Saethre-Chotzen syndrome alter protein kinase A-mediated phosphorylation of Twist1, suggesting that misregulation of Twist1 dimerization through either stoichiometric or post-translational mechanisms underlies phenotypes of individuals with Saethre-Chotzen syndrome [6].
• Saethre-Chotzen syndrome is one of the most common autosomal dominant disorders of craniosynostosis in humans and is characterized by craniofacial and limb anomalies [7].
• All mutations described so far for other craniosynostotic syndromes with associated limb anomalies--Jackson-Weiss, Pfeiffer, and Apert--also occur in the extracellular domain of FGFR2, as well as FGFR1 for Pfeiffer syndrome [8].
• A mutation in FGFR1 has been established in several families with Pfeiffer syndrome, where craniosynostosis is associated with specific digital abnormalities [9].

Chemical compound and disease context of Acrocephalosyndactylia

• The arginine residue at position 253 in the linker region between the Ig-like domains D2 and D3 in the wild type fly and worm sequences is particularly striking, as the Pro253Arg mutation in humans is responsible for Apert syndrome [10].
• This finding confirms the involvement of mutations of FGFR2 exon IIIa in Pfeiffer syndrome, and emphasizes both the extensive heterogeneity of the FGFR2 mutations that result in the Pfeiffer phenotype and the perturbations caused by unpaired cysteine residues in receptor dimerization and transduction of the FGFs signal [11].
• Successful treatment of the acne of Apert syndrome with isotretinoin [12].
• Novel mutation in the tyrosine kinase domain of FGFR2 in a patient with Pfeiffer syndrome [13].

Biological context of Acrocephalosyndactylia

• We now report point mutations in FGFR2 in seven sporadic Pfeiffer syndrome patients [9].
• Increased bone formation and decreased osteocalcin expression induced by reduced Twist dosage in Saethre-Chotzen syndrome [14].
• We have previously provisionally assigned the gene for one such condition, Saethre-Chotzen syndrome (ACS III), to chromosome 7p [15].
• Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations [16].
• De novo alu-element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome [1].

Anatomical context of Acrocephalosyndactylia

• The Saethre-Chotzen syndrome is characterized by premature fusion of cranial sutures resulting from mutations in Twist, a basic helix-loop-helix (bHLH) transcription factor [14].
• Crouzon syndrome and Pfeiffer syndrome are both autosomal dominant craniosynostotic disorders that can be caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene [17].

Gene context of Acrocephalosyndactylia

• Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome [18].
• Here we show that mice carrying a Pro250Arg mutation in Fgfr1, which is orthologous to the Pfeiffer syndrome mutation in humans, exhibit anterio-posteriorly shortened, laterally widened and vertically heightened neurocraniums [19].
• The crystal structure, of Pro252Arg FGFR1c in complex with FGF2, demonstrates that the enhanced ligand binding is due to an additional set of receptor-ligand hydrogen bonds, similar to those gain-of-function interactions that occur in the Apert syndrome Pro253Arg FGFR2c-FGF2 crystal structure [20].
• However, unlike the Apert syndrome Pro253Arg FGFR2c mutant, neither the Pfeiffer syndrome Pro250Arg FGFR1c mutant nor the Muenke syndrome Pro250Arg FGFR3c mutant bound appreciably to FGF7 or FGF10 [20].
• Mutations in snail family genes enhance craniosynostosis of Twist1 haplo-insufficient mice: implications for Saethre-Chotzen Syndrome [21].

Analytical, diagnostic and therapeutic context of Acrocephalosyndactylia

• Linkage mapping was carried out excluding allelism to Saethre-Chotzen syndrome at 7p21, craniosynostosis Boston type at 5q34-q35, Jackson-Weiss and Crouzon syndromes at 10q24-q25 and Pfeiffer syndrome mapping near 8cen [22].
• The clinical variability of Pfeiffer syndrome as well as other causes of craniosynostosis can make a prenatal diagnosis based on sonography alone difficult [23].
• To obtain better functional and aesthetic results in midfacial distraction in adults and adolescents with syndromic craniosynostosis, dual Le Fort III minus I and Le Fort I midfacial distraction osteogenesis was performed in four cases (in two patients with Crouzon syndrome and in two patients with Apert syndrome) [24].
• The nosological aspects of this fetus and the differential diagnosis of well-described craniosynostosis syndromes with characteristic craniofacial growth patterns (Crouzon syndrome, Jackson-Weiss syndrome, Apert syndrome, Saethre-Chotzen syndrome, Pfeiffer syndrome) are discussed [25].
• After traditional bifrontal craniotomy, an abnormal displacement growth pattern was observed from age 14 to 45 months in the patient with syndromic craniosynostosis (Pfeiffer syndrome) [26].

References