Progressive synosteosis in Apert's syndrome (acrocephalosyndactyly), with a description of roentgenographic changes in the feet.
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Acrocephalosyndactylia↗
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Down-regulation of ubiquitin ligase Cbl induced by twist haploinsufficiency in Saethre-Chotzen syndrome results in increased PI3K/Akt signaling and osteoblast proliferation.
Genetic mutations of Twist, a basic helix-loop-helix transcription factor, induce premature fusion of cranial sutures in Saethre-Chotzen syndrome (SCS). We report here a previously undescribed mechanism involved in the altered osteoblastogenesis in SCS. Cranial osteoblasts from an SCS patient with a Twist mutation causing basic helix-loop-helix deletion exhibited decreased expression of E3 ubiquitin ligase Cbl compared with wild-type osteoblasts. This was associated with decreased ubiquitin-mediated degradation of phosphatidyl inositol 3 kinase (PI3K) and increased PI3K expression and PI3K/Akt signaling. Increased PI3K immunoreactivity was also found in osteoblasts in histological sections of affected cranial sutures from SCS patients. Transfection with Twist or Cbl abolished the increased PI3K/Akt signaling in Twist mutant osteoblasts. Forced overexpression of Cbl did not correct the altered expression of osteoblast differentiation markers in Twist mutant cells. In contrast, pharmacological inhibition of PI3K/Akt, but not ERK signaling, corrected the increased cell growth in Twist mutant osteoblasts. The results show that Twist haploinsufficiency results in decreased Cbl-mediated PI3K degradation in osteoblasts, causing PI3K accumulation and activation of PI3K/Akt-dependent osteoblast growth. This provides genetic and biochemical evidence for a role for Cbl-mediated PI3K signaling in the altered osteoblast phenotype induced by Twist haploinsufficiency in SCS.
Acrocephalosyndactylia↗
Sleep apnea and sleep-related breathing disorders in patients with craniofacial synostosis.
Seventeen patients with craniofacial synostosis (CFS) have been treated at the Department of Plastic and Reconstructive Surgery at Osaka Medical College during the past 10 years. Six patients were thoroughly evaluated at the Department of Otolaryngology by polysomnography (PSG), cephalometric X-ray and nasopharyngoscopy during sleep. In 4 of the patients PSG showed obstructive sleep apnea syndromes (OSAS). Heavy snoring without apnea and paradoxical respiration were noted in the other 2 patients. Thus, all of the patients had sleep-related breathing disorders (SRBD). It is assumed that the incidence of SRBD in CFS is high. Cephalometric analysis and profilogram showed maxillomandibular hypoplasia in each patient, and it was assumed that the main cause of SRBD in CFS was stenosis of the upper airway tract caused by maxillo-mandibular hypoplasia. Nasopharyngoscopy was performed during sleep in 2 patients with OSAS secondary to CFS. One patient with adenotonsillar hypertrophy had nasopharyngeal obstruction and another patient whose posterior airway space (PAS) on cephalometric radiograph was 3 mm (normal value: 11 mm) had obstruction at the tongue base.
Acrocephalosyndactylia↗
Carpenter's syndrome (acrocephalopolysyndactyly type II) with normal intelligence.
A 6-year-old girl with Carpenter's syndrome is reported who, in spite of a considerably distorted and small calvarium at birth, has normal mental development. Cranio-facial surgery was carried out in infancy, but its role in respect to mental development is difficult to assess since unoperated patients with normal intelligence and Carpenter's syndrome have been widely reported. Nevertheless, early cranio-facial surgery is recommended for cosmetic reasons.
Acrocephalosyndactylia↗
Syndromes of facial clefting.
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Abnormalities, Multiple↗
Gradual bone distraction in craniosynostosis. Preliminary results in seven cases.
Seven patients with craniosynostosis (mean age 8 years, Apert syndrome, n = 4, Crouzon's disease, n = 3) underwent lengthening of the skull by gradual bone distraction. Three patients (group A) were treated by coronal craniectomy reaching the orbital fissure and gradual bone distraction. The other four (group B) underwent monobloc craniofacial disjunction and gradual bone distraction. The patients' progress was monitored clinically as well as by radiographs and photographs. The results showed that craniofacial disjunction followed by gradual bone distraction produced complete correction of exophthalmus and an improvement in the functional and aesthetic aspects of the middle third of the face without the need for bone grafts.
Acrocephalosyndactylia↗
Elajalde-Saldino syndrome with eosinophilia.
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Acrocephalosyndactylia↗
Acrocephalospondylosyndactyly--a possible new syndrome: analysis of the vertebral and intervertebral components.
Apert-Crouzon syndrome (formerly ACS type 2; 10130) is now considered a subset of autosomal dominant Apert acrocephalosyndactyly type 1 (10120), with features of craniosynostoisis, syndactyly of all extremities, maxillary hypoplasia, "parrot-beaked" nose, hypertelorism, exophthalmos, external strabismus, and short upper lip. We report a 3 1/2-month-old infant with features of Apert syndrome, plus thoracic vertebral anomalies radiographically similar to those seen in spondylothoracic dysplasia, a condition in which block thoracic vertebrae with widely open neural arches and a fan-shaped thoracic cage are found. Our patient also had flared metaphyseal ends of humeri, dislocated radii with immobile elbows, an unusual tail-like protuberance in the coccygeal area, and a solid cartilaginous tracheal wall. To date, in ongoing reviews of radiographs of other patients with acrocephalosyndactyly or acrocephalopolysyndactyly complexes and of relevant literature, we have not identified other patients with these findings. The vertebrae and intervertebral discs of the patient in this report, three patients with Jarcho-Levin syndrome, and one with Apert syndrome were measured from anteroposterior chest radiographs; the findings clearly distinguish the condition in our patient from Jarcho-Levin syndrome or Apert syndrome.
Abnormalities, Multiple↗
Tracheal cartilaginous sleeve.
Tracheal cartilaginous sleeve (TCS) is a rare congenital malformation in which discrete cartilaginous rings are replaced by a grossly uninterrupted cartilaginous sleeve. Seven previous patients with TCS have been reported in the world literature; in each instance, TCS was associated with craniosynostosis (CS). We report details of five additional patients with TCS, of whom four had a dominantly inherited CS. Gross examination of the available tracheas and bronchi demonstrates a cartilaginous sleeve with posterior interruption but lacking a normal pars membranacea. The stained and cleared tracheas all demonstrate variable ring formation, usually limited to the posterolateral aspect. The functional significance of TCS, if any, is unknown. No data are available on the prevalence of TCS in CS syndromes. The formation of TCS implies a common mesenchymal defect in which normally discrete structures fuse and is probably analogous to other mesenchymal abnormalities seen in these patients.
Abnormalities, Multiple↗
Lessons from a case of kleeblattschädel. Case report.
The authors describe the clinical, radiological, and postmortem findings of a case of cloverleaf skull syndrome. The presence of hindbrain herniation, abnormal cervical segmentation, and atlantoaxial subluxation illustrate the anatomical complexity of the skull base and the craniocervical junction that may coexist in this condition. Unavoidable division of occipital emissary veins during elevation of the skin flap at the time of vault remodeling surgery led to an acute and, ultimately, fatal rise in intracranial pressure. Postmortem examination and review of magnetic resonance imaging revealed an anomalous pattern of venous drainage of the intracranial structures that appeared to have developed in response to venous obstruction, secondary to intraosseous venous sinuses and stenosis of the jugular foramina. The relationship between venous hypertension, hindbrain herniation, and hydrocephalus in this situation is reviewed, and the implications for evaluation and management of this vexing disorder are discussed.
Acrocephalosyndactylia↗
Chronic tonsillar herniation in Crouzon's and Apert's syndromes: the role of premature synostosis of the lambdoid suture.
The incidence of chronic tonsillar herniation (CTH) was evaluated with magnetic resonance imaging in 44 patients with Crouzon's syndrome and 51 with Apert's syndrome; the incidence was 72.7% in Crouzon's syndrome and 1.9% in Apert's syndrome. All the patients with Crouzon's syndrome and progressive hydrocephalus had CTH, but of 32 individuals with Crouzon's syndrome and CTH, only 15 had progressive hydrocephalus. Five patients with Apert's syndrome were treated for progressive hydrocephalus; none had CTH. The patterns of suture closure in these two groups of patients were studied, and significant differences in coronal, sagittal, and lambdoid sutures were found between patients with Crouzon's and Apert's syndromes. In Crouzon's syndrome, significant differences in the pattern of lambdoid suture closure were found between the groups with and without CTH; in the group with CTH, the lambdoid closure appeared earlier. The authors propose that the high incidence of individuals with CTH who have Crouzon's syndrome is related to the premature synostosis of the lambdoid suture in the first 24 months of age.
Acrocephalosyndactylia↗
Prognosis for mental function in Apert's syndrome.
The factors involved in the mental development of patients with Apert's syndrome were studied by the authors, focusing on the age of the patient at operation, associated brain malformations, and the quality of the family environment. Overall, 32% of patients with significant follow-up review had an intelligence quotient (IQ) greater than 70. Age at operation appeared to be the main factor associated with changes in mental development: final IQ was greater than 70 in 50% of patients operated on before 1 year of age versus only 7.1% in patients operated on later in life (p = 0.01). Malformations of the corpus callosum and size of the ventricles played no role in the final IQ, whereas anomalies of the septum pellucidum had a significant effect, with the proportion of patients with an IQ over 70 increasing more than twofold in patients with a normal septum compared with patients with septal anomalies (p < 0.04). Quality of the family environment was the third factor involved in intellectual achievement: only 12.5% of institutionalized children reached a normal IQ level compared to 39.3% of children from a normal family background.
Acrocephalosyndactylia↗
Hydrocephalus and craniosynostosis.
OBJECT: A retrospective study of 1727 cases of craniosynostosis was undertaken to determine the interrelationship between abnormal cerebrospinal fluid (CSF) hydrodynamics and craniosynostosis. METHODS: The patients were divided into two groups: nonsyndromic craniosynostosis and syndromic craniosynostosis. Cases of occipital plagiocephaly without suture synostosis and cases of shunt-induced craniosynostosis were excluded from the study. The majority of patients (1297) were treated surgically for their cranial deformity; 95% of these patients had a postoperative follow-up review period lasting 5 years. Clinical and radiographic charts covering the time from presentation through the follow-up period were reviewed. CONCLUSIONS: Abnormal intracranial CSF hydrodynamics was found in 8.1% of the patients (3.4% of whom had received shunts and 4.5% of whom had not). Three types of CSF hydrodynamic disturbance were observed: progressive hydrocephalus with ventricular dilation, nonprogressive ventriculomegaly, and dilation of the subarachnoid spaces. Hydrocephalus occurred much more frequently in patients with syndromic craniosynostosis (12.1%) than in those with isolated craniosynostosis (0.3%). In fact, patients with kleeblattschädel exhibited hydrocephalus as a constant feature and patients with Crouzon's syndrome were far more likely to have hydrocephalus than those with other syndromes. In Apert's syndrome, ventricular dilation occurred very frequently, but it was almost always nonprogressive in nature. In most cases of syndromic craniosynostosis, venous sinus obstruction and/or chronic tonsillar herniation were found. Their role in the pathophysiology of hydrocephalus in craniosynostosis is discussed.
Acrocephalosyndactylia↗
Clinical variability in patients with Apert's syndrome.
OBJECT: Apert's syndrome is characterized by faciocraniosynostosis and severe bony and cutaneous syndactyly of all four limbs. The molecular basis for this syndrome appears remarkably specific: two adjacent amino acid substitutions (either S252W or P253R) occurring in the linking region between the second and third immunoglobulin domains of the fibroblast growth factor receptor (FGFR)2 gene. The goal of this study was to examine the phenotype/genotype correlations in patients with Apert's syndrome. METHODS: In the present study, 36 patients with Apert's syndrome were screened for genetic mutations. Mutations were detected in all cases. In one of the patients there was a rare mutation consisting of a double-base pair substitution in the same codon (S252F). A phenotypical survey of our cases was performed and showed the clinical variability of this syndrome. In two patients there was no clinical or radiological evidence of craniosynostosis. In two other patients with atypical forms of syndactyly and cranial abnormalities, the detection of a specific mutation was helpful in making the diagnosis. CONCLUSIONS: The P253R mutation appears to be associated with the more severe forms, with regard to the forms of syndactyly and to mental outcome. The fact that mutations found in patients with Apert' s syndrome are usually confined to a specific region of the FGFR2 exon IIIa may be useful in making the diagnosis and allowing genetic counseling in difficult cases.
Acrocephalosyndactylia↗
Enigma of raised intracranial pressure in patients with complex craniosynostosis: the role of abnormal intracranial venous drainage.
OBJECT: In this study the authors investigated whether patterns of intracranial venous drainage in children with complex craniosynostosis associated with raised intracranial pressure (ICP) were abnormal and, thus, could support the theory that venous hypertension is a major contributor to raised ICP that can lead to impaired visual function or even blindness in these patients. METHODS: The authors analyzed the anatomy of intracranial venous drainage as demonstrated in the results of 24 angiography studies obtained in 23 patients, all of whom had either a craniosynostosis-related syndrome (18 patients) or a nonsyndromic multisutural synostosis (five patients). Twenty-one patients had experienced raised ICP (in 19 patients diagnosis was based on invasive ICP monitoring and in two patients on clinical grounds alone) 1 to 6 weeks before undergoing angiography. Of the two remaining patients (both with Apert syndrome) whose ICP monitoring was normal immediately before angiography, each had undergone two previous cranial vault expansion procedures. On results of 18 angiography studies a 51 to 99% stenosis or no flow at all could be observed in the sigmoid-jugular sinus complex either bilaterally (11 patients) or unilaterally (seven patients). In 11 of these patients a florid collateral circulation through the stylomastoid emissary venous plexus was also seen. Two angiography studies were performed in one patient with Crouzon syndrome. A comparison of the two studies demonstrated a progression of the abnormal venous anatomy in that case. The authors found no obvious correlation between each patient's baseline ICP and the degree of abnormality of their venous anatomy, as judged on the basis of a venous-phase angiography severity score. CONCLUSIONS: Based on their findings, the authors assert that in children with complex forms of craniosynostosis in whom other factors, such as hydrocephalus, are absent, abnormalities of venous drainage that particularly affect the sigmoid-jugular sinus complex produce a state of venous hypertension that, in turn, is responsible for the majority of cases of raised ICP. The incidence of these changes is unknown, but an analysis of the ages of the children in this study indicated that the period of particular vulnerability to the effects of venous hypertension lasts until the affected child is approximately 6 years old. After that age the collateral venous drainage through the stylomastoid plexus will likely become sufficient to allow ICP to normalize.
Acrocephalosyndactylia↗
Dynamic cranioplasty for brachycephaly in apert syndrome: long-term follow-up study.
OBJECT: Brachycephaly is a characteristic feature of Apert syndrome. Traditional techniques of cranioplasty often fail to produce an acceptable morphological outcome in patients with this condition. In 1996 a new surgical procedure called "dynamic cranioplasty for brachycephaly" (DCB) was reported. The purpose of the present study was to analyze perioperative data and morphological long-term results in patients with the cranial vault deformity of Apert syndrome who were treated with DCB. METHODS: Twelve patients have undergone surgery performed using this technique since its introduction in 1991 (mean duration of follow-up review 60.2 months). Eleven patients had bicoronal synostosis and one had a combined bicoronal-bilambdoid synostosis. Perioperative data and long-term evolution of skull shape visualized on serial cephalometric radiographs were analyzed and compared with normative data. Changes in mean skull proportions were evaluated using a two-tailed paired-samples t-test, with differences being considered significant for probability values less than 0.01. The mean operative blood transfusion was 136% of estimated red cell mass (ERCM) and the mean postoperative transfusion was 48% of ERCM. The mean operative time was 218 minutes. The duration of stay in the intensive care unit averaged 1.7 days and the mean hospital stay was 11.8 days. There were no incidences of mortality and few complications. An improvement in skull shape was achieved in all cases, with a change in the mean cephalic index from a preoperative value of 90 to a postoperative value of 78 (p = 0.000254). CONCLUSIONS: Dynamic cranioplasty for brachycephaly is a safe procedure, yielding high-quality morphological results in the treatment of brachycephaly in patients with Apert syndrome.
Acrocephalosyndactylia↗
Negative autoregulation of fibroblast growth factor receptor 2 expression characterizing cranial development in cases of Apert (P253R mutation) and Pfeiffer (C278F mutation) syndromes and suggesting a basis for differences in their cranial phenotypes.
OBJECT: Heterogeneous mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause a range of craniosynostosis syndromes. The specificity of the Apert syndrome-affected cranial phenotype reflects its narrow mutational range: 98% of cases of Apert syndrome result from an Ser252Trp or Pro253Arg mutation in the immunoglobulin-like (Ig)IIIa extracellular subdomain of FGFR2. In contrast, a broad range of mutations throughout the extracellular domain of FGFR2 causes the overlapping cranial phenotypes of Pfeiffer and Crouzon syndromes and related craniofacial dysostoses. METHODS: In this paper the expression of FGFR1, the IgIIIa/c and IgIIIa/b isoforms of FGFR2, and FGFR3 is investigated in Apert syndrome (P253R mutation)- and Pfeiffer syndrome (C278F mutation)-affected fetal cranial tissue and is contrasted with healthy human control tissues. Both FGFR1 and FGFR3 are normally expressed in the differentiated osteoblasts of the periosteum and osteoid, in domains overlapped by that of FGFR2, which widely include preosseous cranial mesenchyme. Expression of FGFR2, however, is restricted to domains of advanced osseous differentiation in both Apert syndrome- and Pfeiffer syndrome-affected cranial skeletogenesis in the presence of fibroblast growth factor (FGF)2, but not in the presence of FGF4 or FGF7. Whereas expression of the FGFR2-IgIIIa/b (KGFR) isoform is restricted in normal human cranial osteogenesis, there is preliminary evidence that KGFR is ectopically expressed in Pfeiffer syndrome-affected cranial osteogenesis. CONCLUSIONS: Contraction of the FGFR2-IgIIIa/c (BEK) expression domain in cases of Apert syndrome- and Pfeiffer syndrome-affected fetal cranial ossification suggests that the mutant activation of this receptor, by ligand-dependent or ligand-independent means, results in negative autoregulation. This phenomenon, resulting from different mechanisms in the two syndromes, offers a model by which to explain differences in their cranial phenotypes.
Acrocephalosyndactylia↗
A case of Pfeiffer syndrome.
Pfeiffer Syndrome is as rare as Apert syndrome in the Western population. This condition is very rare in the Asian population and has not been previously reported in Korea. The authors report with a review of literature the case of a newborn baby with Pfeiffer syndrome, manifested by bicoronal craniosynostosis, broad thumbs, and big toes. The infant also had bilateral syndactyly of the fingers and toes, mild proptosis, choanal hypoplasia and maxillary hypoplasia.
Acrocephalosyndactylia↗