Ser351Cys mutation in the fibroblast growth factor receptor 2 gene results in severe Pfeiffer syndrome.
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Acrocephalosyndactylia↗
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FGFR1 Pfeiffer syndrome without craniosynostosis: an additional case report.
Pfeiffer syndrome is an autosomal dominant condition classically encompassing both craniosynostosis and digital abnormalities of the hands and feet. Individuals with Pfeiffer syndrome may have mutations within either fibroblast growth factor receptor 1 gene (FGFR1) or FGFR2. FGFR1 mutations often result in less severe craniofacial involvement and hand abnormalities. We report a four-generation family with an FGFR1 P252R mutation, who have typical hand and feet skeletal features of Pfeiffer syndrome without craniofacial involvement. This is the third family in the literature in which no family members have craniofacial features of Pfeiffer syndrome. The absence of craniosynostosis should not preclude the consideration of FGFR mutation analysis in cases in which digital features are characteristic of the craniosynostosis syndromes.
Acrocephalosyndactylia↗
Treatment of the hands and feet in Apert syndrome: an evolution in management.
Apert syndrome is a relatively uncommon condition that is instantly recognizable on the basis of the pan-syndactylies involving both the hands and feet. For more than 10 years, the treatment of Apert syndrome hand and foot anomalies was approached in a comprehensive manner, with attempts to maximize the final results and minimize the total number of operations. Numerous conventions were abandoned in the development of this approach, with the introduction of some new methodologies, including (1) release of all 10 fingers, and toes, in only two operations, (2) elimination of routine digital amputations, (3) abandonment of the zigzag incision in favor of straight-line release, (4) substitution of equal-length anterior and posterior flaps for the long dorsal web space lining flap, (5) leaving of small areas of exposed bone without vascularized tissue coverage, and (6) performance of midphalangeal osteotomies, among older children, to improve hand function. Fifty-seven children with Apert syndrome have been treated at the author's center since 1990, and 43 underwent surgical treatment of their hands and feet by a single surgeon. Treatment can be separated into two phases, early (syndactyly releases) and late (functional osteotomies). Seventeen of those 43 patients were treated at the author's center from birth (type I, 11 patients; type II, two patients; type III, four patients), and 10 fingers and 10 toes were achieved for all patients in two operations. No digital amputations were performed for any of the 43 patients. However, four of 26 patients (15 percent) not treated at the author's center from birth had undergone at least one digital amputation before coming to the center. Twenty-two of those 26 patients required a two-stage syndactyly release to accomplish the separation of all 10 fingers and toes. Aside from the patients who had previously undergone amputations, all other patients successfully achieved 10 fingers and toes, except for one patient (38 of 39 patients, 97 percent). The average operative time for the first-stage syndactyly release of the hands and feet was 4 hours 11 minutes (range, 185 to 300 minutes), and that for the second stage was 3 hours 49 minutes (range, 160 to 300 minutes). Twenty-eight hands were treated with functional osteotomies, which involved permanent angulation of the fused phalanges at the proximal interphalangeal level, to create a "position of function" and provide pulp-to-pulp pinch. In addition, targeted osteotomies of the feet were performed for many of these patients, to decrease pain with walking. There were no major complications. Minor complications included one reexploration because of bleeding, early in the series. There were 13 incomplete secondary syndactylies that required a subsequent operative release (10 spaces treated at the author's center and three treated elsewhere), of a total of 342 spaces (3 percent author incidence). There were no scar contractures or functional limitations that required release. This distinctive protocol seemed to result in improved functional outcomes, with a reduction in the total number of operative procedures.
Acrocephalosyndactylia↗
Halo distraction of the Le Fort III in syndromic craniosynostosis: a long-term assessment.
BACKGROUND: Little is known about long-term outcomes after Le Fort III halo distraction, such as indications for distraction, amount of relapse, and long-term maxillary growth. METHODS: During a 5-year period, 51 Le Fort III osteotomies were performed; 41 of these were by halo distraction for the treatment of craniofacial dysostosis (Apert syndrome, 25; Crouzon syndrome, nine; Pfeiffer syndrome, four; other, three). Patient records were reviewed and 104 cephalograms were analyzed. RESULTS: The average treatment age was 8 years, and the average hospitalization was 5.3 days (3.6 days for the second half of this series). The average distraction was 26 mm (range, 14 to 44 mm), the sella-nasion-subspinale angle increased from 70 degrees to 87 degrees, the upper incisal edge advanced 18 mm, and the vertical distance between nasion and point A increased by 7 mm. There was no maxillary relapse at 1 year and no measurable forward maxillary growth for up to 5 years, although the maxilla did grow vertically (p < or = 0.001). Three patients underwent tracheostomy removal; sleep studies showed the average respiratory disturbance index improved from 24 to 11 (p = 0.004) and the minimum oxygen saturation increased from 81 to 89 (p = 0.006). Three early patients had incomplete advancements. CONCLUSIONS: The maxilla remained stable after Le Fort III halo distraction without any relapse, and no anterior growth was observed up to 5 years postoperatively. This procedure effectively eliminated sleep apnea in most children, and had a low overall complication rate that declined with experience. Most distracted patients will likely avoid the traditional second Le Fort III.
Acrocephalosyndactylia↗
Hypertelorism: the importance of three-dimensional imaging and trends in the surgical correction by facial bipartition.
BACKGROUND: The technique of facial bipartition has been considered a great advance in achieving a more natural appearance in hypertelorism correction. METHODS: Fourteen patients who had undergone hypertelorism correction by facial bipartition were retrospectively studied to analyze the role of three-dimensional computed tomographic reconstruction in the evaluation of the deformity and preoperative planning. The procedure and surgical details that can improve the outcome were described. A reproducible set of three-dimensional measurements that can help in preoperative patient evaluation was determined based on information obtained using the Analyze/AVW 3.1 system (Biomedical Imaging Resource, Mayo Foundation, Rochester, Minn.). RESULTS: In this series, the most common diagnosis was frontonasal dysplasia (64.3 percent). Five patients had second-degree (35.7 percent) and nine had third-degree hypertelorism (64.3 percent). The three-dimensional scans were shown to be highly accurate in predicting the degree of deformity. There was a significant difference in the preoperative and postoperative interdacryon distance and midface height (p < 0.05) but not in the bitemporal distance (p = 0.08). The simulation correlated significantly with the postoperative result when interdacryon distance and midface height were analyzed (0.736 and 0.999). CONCLUSIONS: Facial bipartition provided a three-dimensional correction of hypertelorism. Three-dimensional imaging can definitely be considered an extra tool for accurate surgical planning and helping the family understand the surgical procedure and the end result.
Acrocephalosyndactylia↗
Clinical and genetic analysis of patients with Saethre-Chotzen syndrome.
BACKGROUND: Saethre-Chotzen syndrome is a craniosynostosis syndrome further characterized by distinctive facial and limb abnormalities. It shows complete penetrance and variable expressivity and has been linked to the TWIST gene on chromosome 7p21; more than 80 different intragenic mutations and, recently, large deletions have been detected in Saethre-Chotzen patients. The aim of this study was to genetically and phenotypically characterize patients with a clinical diagnosis of Saethre-Chotzen syndrome. METHODS: Patients with a clinical diagnosis as well as those with a genetic diagnosis of Saethre-Chotzen syndrome (n = 34) were included in the study. RESULTS: The study showed that the important features of Saethre-Chotzen syndrome are brachycephaly (occurring in 74 percent of patients), a broad, depressed nasal bridge (65 percent), a high forehead (56 percent), ptosis (53 percent), and prominent auricular crura (56 percent). Furthermore, using different molecular techniques, pathogenic mutations in the TWIST gene were identified in 71 percent of patients. CONCLUSIONS: Patients with deletions of the TWIST gene did not differ from those with intragenic TWIST mutations in frequency or severity of craniofacial abnormalities. However, they did distinguish themselves by the presence of many additional anomalies and diseases and--most importantly--the high frequency of mental retardation, which was borderline significant. The authors conclude that when using stringent inclusion criteria for studies of Saethre-Chotzen syndrome, patients who have a pathogenic mutation of the TWIST gene should be excluded.
Acrocephalosyndactylia↗
Cranial vault distraction: its illusionary effect and limitation.
BACKGROUND: Distraction osteogenesis has some advantages, such as less hazardous complications, less scarring, and fewer bone defects. However, it has not been fully accepted yet because of a unidirectional expansion along the distraction device. Because cranial expansion is limited by scalp tension and soft-tissue scarring, undercorrection of the cranium and relapse of the vault deformities have occasionally been seen on long-term follow-up. These patients also had so much bone defect that the donor bone was inadequate for immediate revisions, and dissection under the scalp was complicated. METHODS: The authors used distraction osteogenesis to treat 12 cases of craniosynostosis. Five patients were syndromic (two cases of Pfeiffer's syndrome, two cases of Crouzon's disease, and one case of Apert's syndrome), and seven were nonsyndromic (four cases of brachycephaly, two cases of scaphocephaly, and one case of plagiocephaly). RESULTS: After only unidirectional expansion without vertical reduction, the shape of the cranium was satisfactorily improved, which might have been an illusion caused by the relative reduction attributed to the elongation by the distraction osteogenesis and, in brachycephaly, alteration of the patient's head position resulting from inclination of the facial plane by forehead advancement. However, in scaphocephaly, the unique deformity in the occipital and frontal regions remained after simple distraction. Distraction osteogenesis should be applied for a narrow cranium because the bone defect and scalp closure could pose problems. Radical reshaping should be used in cases of sufficient donor bone and scalp closure. Although additional surgery is unavoidable for device removal, minor revisions can be performed for revision of the irregularity at that time. CONCLUSION: Except for prolonged treatment, based on minimally invasive operations, distraction cranioplasty might be applied extensively in cases of craniosynostosis.
Acrocephalosyndactylia↗
Neuropsychological diversity in Apert syndrome: a comparison of cognitive profiles.
Apert syndrome is characterized by craniosynostosis, central nervous system anomalies, midface hypoplasia, and syndactyly. Current research has focused on genetic and neurologic correlates. Cognitive assessment has been primarily limited to global intellectual evaluations, which can fail to detect the diverse cognitive attributes of these children at an individual level. This report describes in detail the neuropsychological profiles of 2 children with Apert syndrome, incorporating clinical, radiographic, molecular and surgical data. One child showed intellectual deficits consistent with a moderate intellectual disability. The second child, while of normal intelligence, displayed neuropsychological deficits associated with anterior-brain-region cognitive functions. These data highlight the diversity of neuropsychological outcomes in Apert syndrome in the same genetic mutation and underline the importance of detailed neuropsychological evaluations as integral to the management protocols of affected individuals.
Acrocephalosyndactylia↗
Apert and Crouzon syndromes: clinical findings, genes and extracellular matrix.
Apert and Crouzon syndromes are well known craniostenosis. In the last 10 years several studies were performed to provide a better understanding of the etiology and pathogenesis of these diseases. Both have an autosomal dominant mode of transmission, and a mutation in the gene encoding for the fibroblast growth factor receptor 2 (FGFR2) is the cause in most patients. However, the fact that the same mutation can produce a wide range of phenotypic expression makes the mechanism of anomalous development more complex. The extracellular matrix (ECM) is composed of proteins, glycosaminoglycans, and cytokines that are secreted in an autocrine and paracrine manner and are able to modify the ECM. Fibroblast growth factors are complexed with heparan sulfate, a component of the ECM, before binding the FGFR2. Data exist about different expressions of cytokines and ECM macromolecule in craniostenosis-derived fibroblasts and osteoblasts. Changes in ECM composition could explain the altered osteogenic process and account for pathologic variations in cranial development in addition to the FGFR2 mutations.
Acrocephalosyndactylia↗
Le Fort III advancement osteotomy in the growing child affected by Crouzon's and Apert's syndromes: presurgical and postsurgical growth.
This is a longitudinal cephalometric study of patients with craniofacial synostosis (Crouzon's and Apert's) syndromes who underwent Le Fort III advancement during early childhood. The objectives of the study were to quantify presurgical growth, surgical results, and surgical stability as well as long-term postsurgical growth. Of the 31 patients operated on during their growth period (less than 10 years of age), 17 had sufficient records to be included in the study: at infancy, before the Le Fort III osteotomy (average age=7.3 years, range: 4.8-10 years), and immediately after surgery. Ten of the patients were followed radiographically long term for an average of 6.1+/-2.7 years (range: 4.5-10.8 years). The presurgical abnormal midfacial vertical growth pattern was accurately described with a progressive class III discrepancy and an increasing exophthalmos. Remarkable postoperative stability of the maxillary segment was observed. After surgery, growth of the midface was measured, together with minimal, if any, anterior growth, similar to the presurgical growth pattern and rate. No actual detrimental or beneficial effect of surgery on subsequent growth was seen. This study quantitatively confirms that the standard Le Fort III osteotomy is a stable and effective but generally not definitive procedure in childhood. This study might also serve as a control sample to compare with groups of patients undergoing distraction osteogenesis to verify the actual advantages and shortcomings of this alternative technique.
Acrocephalosyndactylia↗
Do Craniosynostosis syndrome phenotypes with both FGFR2 and TWIST mutations have a worse clinical outcome?
We present three cases with both FGFR2 mutations and novel TWIST sequence variants. The clinical outcome in this cohort is compared with that in individuals with a single mutation.
Acrocephalosyndactylia↗
Additional distraction osteogenesis after conventional fronto-orbital advancement.
In the conventional fronto-orbital advancement method, there is a limit to advancement because of scalp skin tension and an absence of a supraorbital bar fixating point. In a case of insufficient advancement after the primary operation, a secondary re-advancement must be performed. In such a condition, additional fronto-orbital advancement by distraction osteogenesis has proved to be very useful. The authors used additional distraction osteogenesis in three infant cases: two of nonsyndromic craniosynostosis and one of Apert's syndrome. They were able to perform these operations safely using their original internal devices. Distraction was started 3 days after the operation. The rate of advancement was 0.5 to 1.0 mm per day. The distraction distances ranged from 16 to 22 mm. They were able to gain enough advancement in all three cases. A reoperation of a fronto-orbital advancement is more difficult than the primary operation because of possible infection, much loss of blood, low blood supply to advanced bones, a tendency of advanced bones to relapse, increased scalp skin tension, and the existence of bone defects. In these poor conditions, distraction osteogenesis has many advantages: good vascularization, no relapsing, a low infection rate, and no need for bony fixating points in the bone defects. Although it is necessary to have a secondary operation to remove the devices and prolonged hospitalization is required, the disadvantages are far outweighed by the many advantages when performing additional fronto-orbital advancement.
Acrocephalosyndactylia↗
The K stitch for hypertelorbitism: improved soft tissue correction with glabellar width reduction.
After correction of moderate to severe hypertelorbitism (greater than 40 mm interdacryon distance) with facial bipartition or orbital box osteotomy, excess glabellar soft tissue and brow width should be addressed. Traditional methods described used a midline excision down the forehead and nasal dorsum, and left an unsightly scar. With a series of 12 patients, the authors document the K stitch technique with no external vertical scar. A mean 38.8% reduction of interbrow distance was noted using this technique. Two patients underwent revisions, and two patients had temporary eyelid ptosis. All patients reported satisfaction once the skin contracture was completed.
Acrocephalosyndactylia↗
Subcranial facial bipartition osteotomy with glabellar reverse V-shaped and temporal approaches instead of the bicoronal approach.
Patients with Apert syndrome show hypertelorism and midfacial hypoplasia, and their features are significantly improved through facial bipartition surgery. In addition, because patients with Apert syndrome demonstrate cranial deformity as well as other deformities, they require multiple surgical interventions throughout their development. We present herein a girl with Apert syndrome for whom subcranial facial bipartition was performed. We could not use the coronal approach because she had a terribly cicatricial scalp and wide calvarial defects caused by previous cranial surgeries carried out at another institution. Therefore, we used the glabellar reverse V-shaped approach and temporal approaches in place of the standard approach. She enjoyed a complication-free intraoperative and postoperative course, and left the hospital on postoperative day 10. Her midfacial segment was repositioned 6 mm anteriorly and 12 mm inferiorly on the cephalometric measurement. Her interpupillary distance was altered from 83 mm preoperatively to 76 mm postoperatively. The reverse V-shaped glabellar approach permits more relaxation of the nasal skin and nasal augmentation that is more reliable, although an inconspicuous scar remains in the prominent area. The temporal approach is also useful, enabling easy zygomatic arch osteotomy and secure pterygo-maxillary separation for pterygo-maxillary separation through an oral approach, allowing chiseling toward the skull base.
Acrocephalosyndactylia↗
Delayed degradation in a resorbable plating system.
Resorbable plating systems are used extensively for craniofacial reconstruction, particularly in children. The systems provide rigid fixation while potentially minimizing the long-term drawbacks of permanent plating systems such as plate "migration," bone growth restriction, and imaging artifact. However, the need for active plate resorption represents both the strength and weakness of these fixation systems. We present four patients who underwent cranial vault remodeling using a resorbable plating system, following which the plates were palpable and observable for at least 2 years postoperatively. All required surgical removal. On gross inspection, the plates had been replaced by an encapsulated spongy material containing yellow, grainy, cloudy liquid. The bone underlying the plates was depressed and irregular in contour when compared with the adjacent bone. Microscopic studies showed a giant cell foreign-body reaction with crystalline material present in the cell vacuoles.
Absorbable Implants↗
Le Fort III distraction osteogenesis in syndromal craniosynostosis.
Midface distraction osteogenesis has become a valuable technique. Although outcome data are available from several craniofacial centers, information regarding perioperative and immediate postoperative course is scarce. This report describes seven children, aged 4 to 17 years, with syndromal craniosynostosis in need of midface advancements. Most were rather complex cases with several previous craniofacial surgeries (mean 4.4 times, range 1-8). The Modular Internal Distraction System (Howmedica Leibinger, Inc., Rutherford, NJ) was used for the gradual Le Fort III advancements. The average midface advancement obtained was 23 mm (range 15-30 mm), resulting in improved facial profile, normalized or improved dental occlusion, reduced exophthalmos, and cessation or a significant decrease in preoperative respiratory problems. The mean length of operation was 354 minutes (range 300-535 minutes), and the mean amount of perioperative blood transfusion needed was 1251 mL (range 450-1800 mL) or 46.0 mL/kg (range 8.2-121.4 mL/kg). Complications included subcutaneous infections inferolaterally to the eye (N = 3) and forehead (N = 1). One patient had worsening of her facial profile and underwent a subsequent fronto-orbital advancement. One patient developed a deviation of the nasal septum and needed a corrective rhinoplasty. One patient developed marked trismus and one needed reoperation and trimming of the anchoring titanium plate on the malar process. In one patient, the lacrimal sac was lacerated, leading to transient epiphora. In most patients, Le Fort III distraction led to a significant improvement in the facial profile. However, surgery is still a major undertaking, with several potential complications. In our hands, the rate of complications is not less than for monobloc advancement. Thus, the choice of operation method is not based on which method is the least risky but on which is best suited for the individual patient.
Acrocephalosyndactylia↗
Le Fort III midfacial distraction using an internal distraction device for syndromic craniosynostosis: device selection, problems, indications, and a proposal for use of a parallel bar for device-setting.
Le Fort III midfacial distraction using internal and external devices is a well-accepted procedure for the midfacial retrusion of craniosynostosis syndrome patients. The authors described 20 consecutive series of Le Fort III midfacial distraction using internal distraction devices. Two types of devices were utilized. One type was a zygoma-skull device (the anterior part of the device is attached to the zygoma, and the posterior part is attached to the skull), which was used in six cases. The other was a zygoma-zygoma device (the anterior and posterior parts of the device are attached to the osteotomized zygoma, respectively), which was used in 14 cases. Subject ages ranged 3-32 years. A 14-20-mm distraction length was obtained by 1 mm/day. Satisfactory distraction of the midface was obtained in 17/20 cases. In 3/6 cases in which a zygoma-skull device was used, an unsatisfactory result was obtained. In these three cases, a fracture of the zygomatico-maxillary suture was encountered, resulting in the Le Fort III portion being left behind. In all 14 cases in which a zygoma-zygoma device was used, a satisfactory result was obtained. During the distraction period, the connection of the distraction device was dislodged, resulting in re-connection in three cases. Slight asymmetry was noticed in two cases without any need for management. In order to obtain parallel setting of the bilateral distraction devices, a newly developed parallel bar was used and demonstrated to be effective.
Acrocephalosyndactylia↗
Deletion of the TWIST gene in a large five-generation family.
In this article, we describe a large five-generation family with characteristics of the Saethre-Chotzen syndrome as well as of the blepharophimosis ptosis epicanthus inversus syndrome. Segregating with their phenotype is a deletion of the chromosome 7p21 TWIST gene locus. The TWIST gene indeed is involved in Saethre-Chotzen syndrome, a craniosynostosis syndrome further characterized by specific facial and limb abnormalities. However, only two members of our family exhibited craniosynostosis. This report demonstrates that the genetics of craniofacial anomalies are less straightforward than they sometimes appear to be. Not only craniosynostosis, but also subtle facial deformities could be indicative of an abnormality of the TWIST gene. In conclusion, the clinical spectrum of genetic abnormalities of the TWIST gene is highly variable. We therefore recommend that genetic analysis of the TWIST gene locus, including fluorescence in situ hybridization, should be considered in familial cases of facial and eyelid abnormalities without the presence of craniosynostosis.
Acrocephalosyndactylia↗