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PubMed2006

Ocular phenotype correlations in patients with TWIST versus FGFR3 genetic mutations.

BACKGROUND/PURPOSE: Despite the similar clinical phenotype of the Saethre-Chotzen and Muenke craniosynostoses, the 2 syndromes are now genotypically distinct. Patients with Saethre-Chotzen and Muenke syndromes carry mutations in the TWIST and fibroblast growth factor receptor (FGFR) 3 genes, respectively. We sought to assess possible ocular phenotypic differences in patients with mutations of either gene previously grouped according to phenotype only. METHODS: A retrospective chart review was performed for 21 children with known mutations of the TWIST (n=10) or the FGFR3 (n=11) genes. Data gathered included patient sex, age, family craniofacial history, craniofacial and ophthalmic surgeries, type of strabismus, ptosis, cycloplegic refraction, visual acuity, the presence of amblyopia, nasolacrimal duct obstruction (NLDO), nystagmus, hypertelorism, epicanthal fold anomalies, and any ocular structural abnormalities. RESULTS: In the TWIST group, ptosis was present in 90%, amblyopia in 70%, horizontal strabismus in 70%, vertical strabismus in 60%, NLDO in 60%, astigmatism in 50%, inferior oblique overaction (IOOA) in 40%, hyperopia in 40%, myopia in 30%, nystagmus in 30%, and optic nerve findings in 30%. In the FGFR3 group, ptosis was present in 36%, amblyopia in 18%, horizontal strabismus in 55%, vertical strabismus in 36%, NLDO in 0%, astigmatism in 9%, IOOA in 45%, hyperopia in 27%, myopia in 18%, nystagmus in 18%, and optic nerve findings in 27%. CONCLUSIONS: Patients with TWIST gene mutations may have more ophthalmic abnormalities, including more strabismus, ptosis, NLDO, astigmatism, vertical deviations, and amblyopia compared with patients with FGFR3 gene mutations.

Abnormalities, Multiple↗
PubMed2006

Ocular abnormalities in Apert syndrome: genotype/phenotype correlations with fibroblast growth factor receptor type 2 mutations.

BACKGROUND/PURPOSE: Apert syndrome, a disorder of craniosynostosis, syndactyly, and other craniofacial malformations, is caused by point mutations (Ser252Trp or Pro253Arg) in the fibroblast growth factor receptor 2 gene. This study's goal was to determine ophthalmic phenotype/genotype correlations in patients with either mutation. METHODS: A retrospective chart review of demographic and ophthalmologic data was performed for 18 children carrying either the S252W (11) or the P253R (7) mutation. Fisher exact tests were performed to determine significance of variable phenotypes between the two mutation groups. RESULTS: In the P253R group, 85% had strabismus (14% required surgery), 71% had ptosis, 43% had amblyopia, 14% had nasolacrimal duct obstruction, 14% had myopia, 14% had hyperopia, and 14% had astigmatism. In the S252W group, 91% had strabismus (64% required surgery), 73% had ptosis, 73% had amblyopia, 100% had nasolacrimal duct obstruction, 36% had myopia, 9% had hyperopia, and 82% had astigmatism. Overall, S252W and P253R groups showed significantly different numbers of patients with strabismus requiring surgery (p = 0.039), superior rectus muscle underaction (p = 0.024), nasolacrimal duct obstruction (p = 0.0002), and astigmatism (p = 0.005). CONCLUSIONS: Compared with patients with the P253R mutation, Apert syndrome patients with the S252W mutation may have more severe ocular phenotypes with a higher likelihood of developing strabismus, especially vertical deviation. They also are more likely to develop astigmatic refractive errors and tearing secondary to nasolacrimal system anomalies.

Acrocephalosyndactylia↗
PubMed2006

Combined push-pull distraction for correction of syndromic midfacial hypoplasia.

PURPOSE: Gradual midfacial advancement, applying the principle of distraction osteogenesis, reduces the restriction of the soft tissues and results in bony consolidation without need for grafting. The midface can be distracted by either pushing it forward, using semiburied devices, or pulling it forward by a rigid external device. For each method there are inherent technical problems, such as controlling the vector of movement, symmetry of advancement, and differential movement of the upper/lower face. We have used a combination of the 2 methods, called "push-pull," in an effort to control the distraction process. The purpose of this paper is to describe our push-pull distraction technique and summarize our early experience. MATERIALS AND METHODS: Ten patients (5 males and 5 females) with a mean age of 11 years 2 months underwent midfacial advancement using push-pull distraction. Two orthodontists, blinded for landmark identification, traced preoperative and postoperative cephalograms and determined linear and angular measurements of midfacial position. A Student t test was used to assess differences between the cephalometric measures on the 2 radiographs. Interexaminer reliability was calculated by an intraclass correlation coefficient. RESULTS: Postdistraction cephalograms were taken a mean of 10 months (range, 3 to 20 months) after removal of the devices. Patients exhibited improvement at all levels of the midface after distraction. There was a statistically significant sagittal advancement from the infraorbital rim to dentoalveolus. The central midface was sufficiently advanced as shown by an improved convexity, nasolabial angle, and upper labial protrusion. There were no significant differences between examiners for any of the measurements in this study. CONCLUSIONS: Push-pull distraction permits 1) equal movement at both the upper and lower facial levels, 2) advancement of the central midface, and 3) symmetric movement of the zygomaticomaxillary complexes. This method also provides a backup, in case one device malfunctions. In combination, the advantages of each device are additive; whereas the weaknesses are not. The push-pull technique is a practical method for midfacial distraction until a better single device is fabricated.

Acrocephalosyndactylia↗
PubMed2004

A case of acrocephalosyndactyly with low imperforate anus.

The authors report a case of a female acrocephalosyndactyly with imperforate anus without fistula, which is rare in girls. Acrocephalosyndactyly is characterized by premature closure of the sutures (craniosynostosis) and fusion or webbing of hands and feet (syndactyly). The most general types of the syndrome are the Apert syndrome and the Pfeiffer syndrome. They usually have some fibroblast growth factor receptor (FGFR) gene mutations, so that acrocephalosyndactyly is thought to be involved in "FGFR-related craniosynostosis." To the authors' knowledge, only 4 cases of anorectal anomaly in acrocephalosyndactyly have been reported in the world. The relationship between anorectal anomaly and the FGFR gene is not clear now, but might be clarified in the future.

Acrocephalosyndactylia↗
PubMed2006

Ophthalmic findings in Apert's syndrome after craniofacial surgery: twenty-nine years' experience.

PURPOSE: To survey the spectrum of ophthalmic morbidity in Apert's syndrome after craniofacial surgery. DESIGN: A retrospective study of patients with Apert's syndrome managed at the Australian Craniofacial Unit from 1975 to 2004. PARTICIPANTS: Sixty-one patients (31 females and 30 males) had final ophthalmic reviews at a mean age of 9.3 years (standard deviation, 9.2; range, 0.2-48.3; median, 8.2 years). METHODS: Patients were identified from the unit database, and case notes were reviewed. Cases that had < or =2 recorded variables were excluded. Demographic details, age at last ophthalmic review, and total craniofacial operations performed were documented. MAIN OUTCOME MEASURES: Best-corrected visual acuity, cycloplegic refractions, strabismus, amblyopia, corneal abnormality, fundoscopic findings, and visually evoked potentials. RESULTS: The average number of craniofacial operations performed was 2 (range, 1-4; median, 2). Visual impairment was found in 54% of patients in at least one eye and in 19% of patients in their better eye. The most common cause was amblyopia, with a prevalence of 35%. Optic atrophy caused visual impairment in 5% of patients and corneal scarring in 8%. Sixty-three percent of patients had strabismus with more esotropia than exotropia. Ametropia was found in 69% of patients (42% were hypermetropic and 27% were myopic). Anisometropia of > or =0.75 diopters was present in 16 cases (50%). CONCLUSIONS: Visual impairment is a common finding in Apert's syndrome and amblyopia is the major cause. Ametropia, astigmatism, anisometropia, and strabismus frequently occur in patients with Apert's syndrome at final ophthalmic review. Although optic atrophy was the major cause of visual loss in the era prior to craniofacial surgery, the prevalence of optic atrophy is low since the adoption of current surgical protocols. Corneal damage also contributed toward visual impairment. Early detection and adequate management of amblyopia, timely decompressive surgery before the presence of optic atrophy, and protection of the cornea should be the management goals of ophthalmologists in craniofacial units managing these patients.

Acrocephalosyndactylia↗
PubMed2005

Pfeiffer syndrome: systemic and ocular implications.

BACKGROUND: In 1964, Pfeiffer described a three-generation family in which eight individuals had a syndrome consisting of craniosynostosis, broad thumbs and great toes, and partial syndactyly of the hands and feet. Pfeiffer syndrome affects males and females equally, and is most commonly a result of de novo mutations, but can be inherited in an autosomal dominant fashion. Pfeiffer syndrome is considered Type V of the five acrocephalosyndactly syndromes (ACS), a group of rare genetic diseases that involve premature closure of the cranial sutures. Cohen, in 1993, further described Pfeiffer syndrome and it's various expression patterns by creating three subgroups of the syndrome. CONCLUSIONS: While Pfeiffer syndrome is clearly a rare disorder, affecting 15 of every 1 million births, there has been a series of publications reviewing the difficult differential diagnosis among Pfeiffer types and between the other acrocephalosyndactly syndromes. While these publications individually focus on a variety of specific systemic and ocular implications of the syndrome, together they encompass the scope of the syndrome. Since Pfeiffer syndrome mainly affects the craniofacial regions, the eye care professional plays an essential role in diagnosis and management. What follows are guidelines to aid in the diagnosis, ophthalmic and functional testing, and management of this disorder.

Acrocephalosyndactylia↗
PubMed2001

Increased osteoblast apoptosis in apert craniosynostosis: role of protein kinase C and interleukin-1.

Apert syndrome is an autosomal dominant disorder characterized by premature cranial ossification resulting from fibroblast growth factor receptor-2 (FGFR-2)-activating mutations. We have studied the effects of the prominent S252W FGFR-2 Apert mutation on apoptosis and the underlying mechanisms in human mutant osteoblasts. In vivo analysis of terminal deoxynucleotidyl transferase-mediated nick-end labeling revealed premature apoptosis of mature osteoblasts and osteocytes in the Apert suture compared to normal coronal suture. In vitro, mutant osteoblasts showed increased apoptosis, as demonstrated by terminal deoxynucleotidyl transferase-mediated nick-end labeling analysis, trypan blue staining, and DNA fragmentation. Mutant osteoblasts also showed increased activity of caspase-8 and effector caspases (-3, -6, -7) constitutively. This was related to protein kinase C activation because the selective protein kinase C inhibitor calphostin C inhibited caspase-8, effector caspases, and apoptosis in mutant osteoblasts. Apert osteoblasts also showed increased expression of interleukin (IL)-1alpha, IL-1beta, Fas, and Bax, and decreased Bcl-2 levels. Specific neutralizing anti-IL-1 antibody reduced Fas levels, Bax expression, effector caspases activity, and apoptosis in mutant cells. Thus, the Apert S252W FGFR-2 mutation promotes apoptosis in human osteoblasts through activation of protein kinase C, overexpression of IL-1 and Fas, activation of caspase-8, and increased Bax/Bcl-2 levels, leading to increased effector caspases and DNA fragmentation. This identifies a complex FGFR-2 signaling pathway involved in the premature apoptosis induced by the Apert S252W FGFR-2 mutation in human calvaria osteoblasts.

Acrocephalosyndactylia↗
PubMed1999

Decreased proliferation and altered differentiation in osteoblasts from genetically and clinically distinct craniosynostotic disorders.

Craniosynostoses are a heterogeneous group of disorders characterized by premature fusion of cranial sutures. Mutations in fibroblast growth factor receptors (FGFRs) have been associated with a number of such conditions. Nevertheless, the cellular mechanism(s) involved remain unknown. We analyzed cell proliferation and differentiation in osteoblasts obtained from patients with three genetically and clinically distinct craniosynostoses: Pfeiffer syndrome carrying the FGFR2 C342R substitution, Apert syndrome with FGFR2 P253R change, and a nonsyndromic craniosynostosis without FGFR canonic mutations, as compared with control osteoblasts. Osteoblasts from craniosynostotic patients exhibited a lower proliferation rate than control osteoblasts. P253R and nonsyndromic craniosynostosis osteoblasts showed a marked differentiated phenotype, characterized by high alkaline phosphatase activity, increased mineralization and expression of noncollagenous matrix proteins, associated with high expression and activation of protein kinase Calpha and protein kinase Cepsilon isoenzymes. By contrast, the low proliferation rate of C342R osteoblasts was not associated with a differentiated phenotype. Although they showed higher alkaline phosphatase activity than control, C342R osteoblasts failed to mineralize and expressed low levels of osteopontin and osteonectin and high protein kinase Czeta levels. Stimulation of proliferation and inhibition of differentiation were observed in all cultures on FGF2 treatment. Our results suggest that an anticipated proliferative/differentiative switch, associated with alterations of the FGFR transduction pathways, could be the causative common feature in craniosynostosis and that mutations in distinct FGFR2 domains are associated with an in vitro heterogeneous differentiative phenotype.

Acrocephalosyndactylia↗
PubMed2002

TWIST inactivation reduces CBFA1/RUNX2 expression and DNA binding to the osteocalcin promoter in osteoblasts.

The Saethre-Chotzen (SC) syndrome is characterized by increased osteogenesis and premature fusion of cranial sutures, resulting from mutations in TWIST, a basic helix-loop-helix transcription factor. The molecular target genes for Twist in osteoblasts are however unknown. We report here that TWIST haploinsufficiency in mutant osteoblasts reduces mRNA and protein levels for CBFA1/RUNX2, a specific osteoblast transcription factor, during both osteoblast cell growth and in vitro osteogenesis. Moreover, this is associated with altered expression of major osteoblast-specific genes. Electrophoretic mobility shift assay (EMSA) showed reduced-binding ability of Cbfa1 to its target OSE2 element in the osteocalcin promoter in mutant osteoblasts. By contrast, TWIST inactivation does not hamper Cbfa1 binding on a similar upstream element present in the alpha1(I) collagen promoter in mutant osteoblasts. This provides the first evidence that TWIST inactivation alters CBFA1/RUNX2 expression and Cbfa1 binding ability to the osteocalcin promoter, indicating that CBFA1/RUNX2 is a target gene for TWIST in human osteoblasts.

Acrocephalosyndactylia↗
PubMed2001

Mutations in the basic domain and the loop-helix II junction of TWIST abolish DNA binding in Saethre-Chotzen syndrome.

Saethre-Chotzen syndrome is an autosomal dominant skull disorder resulting from premature fusion of coronal sutures (craniosynostosis). It is caused by mutations in the TWIST gene encoding a basic Helix-Loop-Helix transcription factor. Here we report on the identification of a novel mutation affecting a highly conserved residue of the basic domain. Unlike nonsense and missense mutations lying within helices, this mutation does not affect protein stability or heterodimerisation of TWIST with its partner E12. However, it does abolish TWIST binding capacity to a target E-box as efficiently as two missense mutations in the loop-helix II junction. By contrast, elongation of the loop through a 7 amino acid insertion appears not to hamper binding to the DNA target. We conclude that loss of TWIST protein function in Saethre-Chotzen patients can occur at three different levels, namely protein stability, dimerisation, and DNA binding and that the loop-helix II junction is essential for effective protein-DNA interaction.

Acrocephalosyndactylia↗
PubMed2001

Sequence analyses and comparative modeling of fly and worm fibroblast growth factor receptors indicate that the determinants for FGF and heparin binding are retained in evolution.

The presence of a large number of fibroblast growth factors (FGFs) and multiple splice forms of their receptors (FGFRs) in higher vertebrates makes the three-dimensional (3D) analysis of FGF interactions with their receptors a formidable task. The situation differs in Caenorhabditis elegans (worm) and Drosophila melanogaster (fruit fly), where only one or two FGF and FGFR sequences have been identified. Structural studies of the FGF-FGFR complexes in such primitive organisms should reveal the basic features of the ligand-receptor interactions as they first emerged through evolution. We have analysed the sequences of worm and fly FGFs and FGFRs and used the recently determined crystal structure of the human FGF1-FGFR2-heparin ternary complex [Pellegrini, L., Burke, D.F., von Delft, F., Mulloy, B. and Blundell, T.L. (2000) Nature 407, 1029-34] to construct 3D models of the homologous complexes. In spite of a low sequence similarity with their human counterparts, key structural features required for ligand-receptor and protein-heparin binding in humans are conserved in the fly and worm FGF-FGFR-heparin complexes. Analyses of the models show that tertiary interactions that are not conserved in sequence are maintained through novel interactions or complementary mutations in the fly and worm sequences. The overall charge distributions observed in the human FGF-FGFR-heparin complex are retained in the fly and worm models. 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. This change may enhance the affinity of receptors for their FGF molecules as observed in Apert mutants.

Acrocephalosyndactylia↗
PubMed1999

Congenital tracheal anomalies in the craniosynostosis syndromes.

The authors present the case of a 12-year-old girl with Pfeiffer's syndrome who underwent successful resection of a tracheal cartilaginous sleeve (TCS) for treatment of sleep apnea. There is growing recognition of the inclusion of TCS in the spectrum of congenital cartilage malformations seen in patients with craniosynostosis (CS) syndromes. This case demonstrates the difficult therapeutic challenge created by the combination of hypopharyngeal and intrinsic airway abnormalities present in CS patients. The early recognition of TCS in these patients may provide the opportunity for improved outcome in this severely affected subgroup of CS patients with otherwise high mortality.

Acrocephalosyndactylia↗