Analysis of fronto-orbital advancement for Apert, Crouzon, Pfeiffer, and Saethre-Chotzen syndromes

The purposes of this study were (1) to document outcome after primary fronto-orbital advancement for the four major eponymous craniosynostotic syndromes (Apert, Crouzon, Pfeiffer, and Saethre-Chotzen) and (2) to identify factors that might influence need for primary and secondary fronto-orbital advancement or foreheadplasty. Also tested was the hypothesis that coincident sagittal synostosis could modulate brachycephaly and affect whether a primary or secondary frontal operation was necessary. Data were collected on age and indications for initial operation, type of primary and secondary frontal procedures, and concomitant sagittal synostosis. Patients initially managed by subcranial Le Fort III were included in the study group but excluded from analysis of fronto-orbital advancement. Patients treated by monobloc advancement or Le Fort III osteotomies with frontal grafting or Anderl modification were assessed as having had primary fronto-orbital advancement. Minimum time to follow-up was 5 years. A total of 126 patients met inclusion criteria. Lateral photographs were examined to assess preoperative and postoperative sagittal position of supraorbital rims-to-globes. Frontal re-advancement was indicated if the corneal apex was anterior to the supraorbital rim. Foreheadplasty was indicated for unacceptable frontal contour and normal supraorbital rim-to-globe relationship. Primary correction for frontal retrusion was not required in 4 percent of Apert (1 of 25), 16 percent of Crouzon (7 of 44), 6 percent of Pfeiffer (2 of 31), and 19 percent of Saethre-Chotzen (5 of 26) patients. Of those infants who had a primary fronto-orbital advancement, reoperation for either supraorbital retrusion or frontal deformity was necessary in all 16 Apert patients and in 5 of 19 Crouzon (26 percent), 10 of 26 Pfeiffer (38 percent), and 13 of 20 Saethre-Chotzen (65 percent) patients (p < 0.001). Age at initial fronto-orbital advancement did not influence reoperative rate. No correlation was found between concomitant sagittal synostosis and necessity for primary or secondary frontal correction (p = 0.22). In summary, phenotypic diagnosis was determinant for outcome as defined by need for secondary fronto-orbital advancement, foreheadplasty, or both. Apert patients had the highest incidence of reoperation for frontal retrusion or forehead contour. Crouzon and Saethre-Chotzen patients were most likely to express a minor phenotype and not require fronto-orbital correction. Coincident sagittal synostosis did not influence frontal projection, as reflected in need for either primary or secondary frontal advancement.     

Prospective anthropometric analysis of sagittal orbital-globe relationship following fronto-orbital advancement in childhood

Fronto-orbital advancement is a common procedure for correction of supraorbital retrusion in patients with coronal craniosynostosis. The aim of this study was two-fold: to quantitate change in the sagittal orbital-globe relationship following fronto-orbital advancement in childhood and to determine the ratio of skeletal-to-soft tissue movement. Soft-tissue points on the orbital rim, orbitale superius (os), orbitale laterale (ol), orbitale inferius (oi), and nasion (n), referenced to apex corneae (ac), were measured preoperatively and postoperatively by a custom-made anthropometer. Intraoperative bony advancement was measured with a caliper. Patients were selected with uniform advancement at the fronto-nasal suture and laterally at the mortise and tenon. Fifteen patients with syndromic craniosynostosis were included in the study (six male, nine female): Apert (n = 2), Crouzon (n = 5), Pfeiffer (n = 4), Saethre-Chotzen (n = 3), and Boston type (n = 1). Average age at operation was 8.7 years (range, 4.5 to 10.5 years). Age, sex, method of fixation, postoperative interval, diagnosis, and skeletal movement were analyzed for possible effect on the magnitude of soft-tissue advancement. Average intraoperative skeletal advancement was 12.1 mm, and average postoperative soft-tissue movement was 10.3 mm (p < 0.001), measured at the midpoint of the supraorbital rims (os). The soft tissue: skeletal movement ratio was 0.9:1. Os was the only point at which soft-tissue advancement could be predicted (Spearman's rank correlation coefficient = 0.67); soft-tissue changes at ol, oi, and n were unpredictable. Skeletal movement was the only determinant of soft-tissue advancement of all variables tested, i.e., diagnosis, age, sex, previous fronto-orbital advancement, and wire versus plate fixation. We make recommendations for calculating the magnitude of fronto-orbital advancement, based on preoperative anthropometry and a soft-to-hard tissue advancement factor.     

Anthropometric study of synostotic frontal plagiocephaly: before and after fronto-orbital advancement with correction of nasal angulation

Surgical correction of synostotic frontal plagiocephaly (unilateral coronal synostosis) focuses on the asymmetry of the forehead and orbits. However, there is controversy regarding whether nasal angulation should be addressed during primary fronto-orbital advancement in infancy. This prospective study was undertaken to answer that question. Preoperative and postoperative anthropometric measurements were obtained for 19 infants with nonsyndromic synostotic frontal plagiocephaly. The measurements included nasal angulation, nasion-to-endocanthion distance, nasion-to-exocanthion distance, and exocanthion-to-tragion distance. All patients underwent bilateral parallelogrammatic fronto-orbital correction. Closing wedge nasal ostectomy was performed for group I (n = 14) and was not performed for group II (n = 5). The average age at the time of follow-up assessments was 3 years 8 months (range, 1 to 14 years) in group I and 5 years 5 months (range, 2 to 15 years) in group II. A statistically significant change was observed for patients who underwent primary correction of nasal angulation; the change correlated with improved naso-orbital symmetry, as judged with nasion-to-endocanthion and nasion-to-exocanthion measurements (p < 0.01 and p < 0.05, respectively). Group I patients exhibited an average preoperative nasal angulation of 9.15 +/- 0.8 degrees that decreased to 3.1 +/- 0.6 degrees postoperatively (p < 0.01). Group II patients exhibited an average preoperative nasal angulation of 6.4 +/- 0.7 degrees that was unchanged postoperatively at 7.2 +/- 1 degrees. The improvement in nasal angulation in group I was particularly striking because the patients in group II exhibited, on average, a lesser degree of preoperative nasal deviation (p < 0.01). This prospective comparison of fronto-orbital correction of synostotic frontal plagiocephaly with and without nasal correction confirmed an earlier study and demonstrated that angulation of the nasal pyramid does not self-correct within 5 years after traditional bilateral fronto-orbital repair. Closing wedge nasal ostectomy results in improved nasal angulation and naso-orbital symmetry, without evidence of distortion or inhibition of nasal growth.     

Surgical correction of Crouzon syndrome

This study analyzes the results of surgical treatment in 39 patients with the Crouzon syndrome. Early fronto-orbital advancement and craniectomy were universally successful in relieving raised intracranial pressure and in reducing ocular proptosis. However, definitive cosmetic correction was not achieved, and early cranial surgery was not able to prevent the development of midface hypoplasia. Thirty-two midfacial advancements have been performed in 30 patients. Sixteen patients had sufficient follow-up data for more than 2 years postoperatively. In all patients, a satisfactory early postoperative result was achieved. In the long-term follow-up group, 11 patients have maintained a satisfactory appearance, while 5 have developed recurrent deformity. Analysis shows this to be associated with a younger age at operation and continued mandibular growth. Frontofacial advancement in adults achieves good long-term results but is associated with a higher incidence of complications.     

Molecular diagnosis of bilateral coronal synostosis.

The authors performed a prospective study evaluating molecular diagnosis in patients with bilateral coronal synostosis. The patients were divided into two groups: (1) those clinically classified as having Apert, Crouzon, or Pfeiffer syndrome and (2) those clinically unclassified and labeled as having brachycephaly. Blood samples were drawn for genomic DNA analysis from 57 patients from 1995 to 1997. Polymerase chain reactions were performed using primers flanking exons in FGFR 1, 2, and 3. Each exon was screened for mutations using single-strand confirmation polymorphism, and mutations were identified by DNA sequencing. Mutations in FGFR2 or FGFR3 were found in all patients (n = 38) assigned a phenotypic (eponymous) diagnosis. All Apert syndrome patients (n = 13) carried one of the two known point mutations in exon 7 of FGFR2 (Ser252Trp and Pro253Arg). Twenty-five patients were diagnosed as having either Crouzon or Pfeiffer syndrome. Five patients with Crouzon syndrome of variable severity had mutations in exon 7 of FGFR2. Fifteen patients (12 with Crouzon, 3 with Pfeiffer) had a mutation in exon 9 of FGFR2, many of which involved loss or gain of a cysteine residue. A wide phenotypic range was observed in patients with identical mutations, including those involving cysteine. Two patients labeled as having Crouzon syndrome had the Pro250Arg mutation in exon 7 of FGFR3. All three patients with the crouzonoid phenotype and acanthosis nigricans had the same mutation in exon 10 of FGFR3 (Ala391Glu). This is a distinct disorder, characterized by jugular foraminal stenosis, Chiari I anomaly, and intracranial venous hypertension. Mutations were found in 14 of 19 clinically unclassifiable patients. Three mutations were in exon 9, and one was in the donor splice site of intron 9 on FGFR2. The most common mutation discovered in this group was Pro250Arg in exon 7 of FGFR3. These patients (n = 10) had either bilateral or unilateral coronal synostosis, minimal midfacial hypoplasia with class I or class II occlusion, and minor brachysyndactyly. No mutations in FGFR 1, 2, or 3 were detected in five patients with nonspecific brachycephaly. In conclusion, a molecular diagnosis was possible in all patients (n = 38) given a phenotypic (eponymous) diagnosis. Different phenotypes observed with identical mutations probably resulted from modulation by their genetic background. A molecular diagnosis was made in 74 percent of the 19 unclassified patients in this series; all mutations were in FGFR2 or FGFR3. Our data and those of other investigators suggest that we should begin integrating molecular diagnosis with phenotypic diagnosis of craniosynostoses in studies of natural history and dysmorphology and in analyses of surgical results.     

Molecular analysis of patients with synostotic frontal plagiocephaly (unilateral coronal synostosis)

Mutations in genes known to be responsible for most of the recognizable syndromes associated with bilateral coronal synostosis can be detected by molecular testing. The genetic alterations that could cause unilateral coronal synostosis are more elusive. It is recognized that FGFR and TWIST mutations can give rise to either bilateral or unilateral coronal synostosis, even in the same family. The authors undertook a prospective study of patients presenting with synostotic frontal plagiocephaly (unilateral coronal synostosis) to Children's Hospital Boston during the period from 1997 to 2000. Mutational analysis was performed on all patients and on selected parents whenever familial transmission was suspected. Intraoperative anthropometry was used in an effort to differentiate those patients in whom a mutation was detected from those in whom it was not. The anthropometric measures included bilateral sagittal orbital-globe distance, inter medial canthal distance, and nasal angulation. Macrocephaly and palpebral angulation were also considered possible determinants. There was a 2:1 female preponderance in 47 patients with synostotic frontal plagiocephaly. Mutations were found in eight of 47 patients: two patients with different single-amino-acid changes in FGFR2, three patients with FGFR3 Pro250Arg, and three patients with TWIST mutations. Another patient had craniofrontonasal syndrome for which a causative locus has been mapped to chromosome X, although molecular testing is not yet available. Two features were strongly associated with a detectable mutation in patients with synostotic frontal plagiocephaly: asymmetrical brachycephaly (retrusion of both supraorbital rims) and orbital hypertelorism. Other abnormalities in the craniofacial region and extremities were clues to a particular mutation in FGFR2, FGFR3, TWIST, or the X-linked mutation. Neither macrocephaly nor degree of nasal angulation nor relative vertical position of the lateral canthi correlated with mutational detection. An additional four patients in this study had either unilateral or bilateral coronal synostosis in an immediate relative and had anthropometric findings that predicted a mutation, and yet no genetic alteration was found. This suggests either that the authors' screening methods were not sufficiently sensitive or that perhaps there are other unknown pathogenic loci. Nevertheless, molecular testing is recommended for infants who have unilateral coronal synostosis, particularly if there are the anthropometric findings highlighted in this study or an otherwise suspicious feature in the child or a parent. Infants with either an identified or a suspected mutation usually need bilateral asymmetric advancement of the bandeau and may be more likely to require frontal revision in childhood.     

Clinical characteristics of patients with unicoronal synostosis and mutations of fibroblast growth factor receptor 3: a preliminary report.

Clinical teaching dictates that isolated unicoronal synostosis is sporadic in occurrence and is possibly related to intrauterine constraint. Despite this, isolated reports document a familial occurrence. It has previously been recognized that there may be a familial pattern of inheritance. Recently, mutations in fibroblast growth factor receptors (FGFRs) have been implicated in several syndromic craniosynostoses. At the authors' institution, mutations in FGFR3, located at chromosome 4p16, have been found to cause coronal synostosis. Two cases of unicoronal synostosis were found to have the same Pro250Arg missense mutation in FGFR3. This finding suggested that all patients with a diagnosis of unicoronal synostosis be screened for the FGFR3 mutation. Between January and December of 1996, patients with a diagnosis of plagiocephaly at the Children's Hospital of Philadelphia were evaluated for the FGFR3 mutation. Thirty-seven patients with unicoronal synostosis had mutational studies. Two additional patients were known to have the FGFR3 mutation at the onset of the study. Of the 37 patients screened, four were found to have the FGFR3 mutation, for a total of six patients with both unicoronal synostosis and the FGFR3 mutation. All patients with unicoronal synostosis were evaluated for facial dysmorphology and operative outcome. The six patients with the FGFR3 mutation had more severe cranial dysmorphology and were more likely to need surgical revision than those without the FGFR3 mutation. The occurrence of the FGFR3 mutation among patients with unicoronal synostosis provides evidence for a genetic basis of certain forms of plagiocephaly. The clinical, radiologic, and molecular findings will be an important addition to the surgical management and counseling of patients with unicoronal synostosis.     

Predictors of velopharyngeal insufficiency in cleft palate orthognathic surgery

The purpose of this study was to appraise the value of preoperative speech assessments, nasopharyngoscopy, and surgical models as predictors of velopharyngeal deterioration after a Le Fort I maxillary advancement in cleft patients. This retrospective study involved a series of 26 cleft patients (16 unilateral complete and nine bilateral complete cleft lips and palates, and one isolated complete cleft palate) who had Le Fort I maxillary advancements between March 1, 1993, and February 7, 1996. The 13 male patients and 13 female patients ranged in age from 15.3 to 46 years (mean age, 19.5 years). Four of these patients had previously undergone pharyngeal flap surgery. Eleven patients had palatal fistulas and one had a bifid uvula that was repaired at the time of orthognathic surgery. Patients with perceived hypernasal speech preoperatively all had hypernasality after advancement (nine of nine). Velopharyngeal insufficiency was observed in two of the 16 whose resonance preoperatively was within normal limits. Speech assessment, therefore, predicted accurately the postoperative status in 23 of 26 patients. Twelve patients had preoperative nasopharyngoscopy that indicated a high risk for velopharyngeal insufficiency (borderline or inadequate closure). Nine of these patients had postoperative velopharyngeal insufficiency. Two of the 14 patients not judged at risk by nasopharyngoscopy developed velopharyngeal insufficiency. Therefore, 21 of the 26 patients were accurately predicted by nasopharyngoscopy. Scoping detected borderline velopharyngeal insufficiency in one patient who was not detected by speech alone. The combined predictive value of speech and scope identified all but one patient who would develop postoperative velopharyngeal insufficiency. The degree of anteroposterior movement determined from surgical models was not predictive of the outcome. Patients with hypernasal speech preoperatively continue to have hypernasal speech after Le Fort I advancement. Preoperative perceptual speech assessment by specially trained speech-language pathologists is an excellent test for predicting postoperative velopharyngeal insufficiency status. Nasopharyngoscopy is an invasive and resource-dependent test that should be assessed with respect to cost effectiveness. In this series, only one patient's risk was more accurately predicted using nasopharyngoscopy than by speech assessment alone.     

Reossification of the orbital wall following ventral translocation of the fronto-orbital bar and cranial vault remodeling.

The purposes of this study were to determine the extent of ossification of the orbit following ventral translocation of the fronto-orbital bar and to find out whether age at the time of the procedure and presence of a concomitant syndrome adversely affect ossification. A retrospective review of 27 patients with craniosynostosis was conducted at the St. Louis Children's Hospital and the Children's Hospital of Oklahoma. Patients with preoperative, perioperative, and postoperative three-dimensional computed tomography scans were included. Eighty-eight percent of the lateral orbital wall defects and 92 percent of the defects within the roof of the orbit ossified completely in the postoperative period. When syndromic patients were compared with nonsyndromic patients (based on clinical findings only), three of the 19 syndromic defects and three of the 30 nonsyndromic defects demonstrated incomplete ossification in the lateral orbital wall (p > 0.05). Similarly, two of the 19 syndromic defects and two of the 30 nonsyndromic defects demonstrated incomplete ossification within the roof of the orbit (p > 0.05). With respect to age at the time of the procedure, four of the 37 defects and two of the 12 defects demonstrated incomplete ossification in the lateral orbital wall for age at the time of the procedure less than 12 months and greater than 12 months, respectively (p > 0.05). Similarly, two of the 37 defects and two of the 12 defects had incomplete ossification within the roof of the orbit for age at the time of the procedure less than 12 months versus more than 12 months, respectively (p > 0.05). Ossification of the orbital wall and roof is complete in the majority of cases within 1 year after the procedure, and neither age at the time of the procedure nor presence of a concomitant syndrome adversely affects ossification of the orbit after ventral translocation of the fronto-orbital bandeau.     

Impact of surgery for stress incontinence on morbidity: cohort study.

OBJECTIVES: To describe the impact of surgery for stress incontinence on the severity of symptoms, other mental and physical symptoms, and overall health. To describe the incidence of postoperative complications. DESIGN: Prospective cohort study; questionnaires completed by patients before and 3, 6, and 12 months after surgery. Questionnaires completed by surgeons both before and after surgery. SETTING: 18 hospitals in the North Thames region. SUBJECTS: 442 women treated surgically for stress incontinence between January 1993 and June 1994. 367 women returned the 3 month questionnaire; 364 returned the 6 month questionnaire; and 359 returned the 12 month questionnaire. 49 surgeons provided perioperative information on 285 of the 442 women and postoperative information on 278. MAIN OUTCOME MEASURES: Stress incontinence symptom severity index, other urinary symptoms, bowel function, mental health, complications, global measures. RESULTS: Most women (288; 87%) reported an improvement in the severity of their stress incontinence, though only 92 (28%) were cured (continent). These improvements persisted for at least 12 months. The likelihood of improvement was similar regardless of whether urodynamic pressure studies had been conducted before surgery. Following surgery, women were less likely to suffer from urinary frequency, nocturia, postvoid fullness, dysuria, and urgency. While mental health improved for 194 (71%), a quarter of women reported deterioration. Only 37 (10%) were satisfied with postoperative pain control. A third experienced one or more complications while in hospital, most commonly difficulty urinating. This problem affected 1 in 11 women after discharge. A year after surgery two thirds of women reported feeling better (251; 72%), that the outcome met or exceeded their expectations (230; 66%), and that they would recommend the operation to a friend in a similar situation (239; 68%), and that they would recommend the operation to a friend in a similar situation (239; 68%). Surgeons tended to be more optimistic about the effects of surgery; they were satisfied with the outcome in 176 (85%) cases and would again treat 245 (94%) of the women as they had done previously. CONCLUSIONS: Although surgery reduces the severity of stress incontinence it is not as effective as current textbooks suggest. Women considering surgery should be provided with more accurate information on the likelihood of an improvement in symptoms and the occurrence of complications, including postoperative pain. Urgency and urge incontinence should not be considered contraindications to surgery. The need for urodynamic assessment before surgery should be reappraised.     

Skeletal stability after Le Fort I maxillary advancement in patients with unilateral cleft lip and palate

Outcomes in 30 adults and adolescents judged skeletally mature who had unilateral cleft lip and palate and underwent Le Fort I advancement were investigated to determine amount and timing of relapse, correlation between advancement and relapse, effect of performing multiple jaw procedures, effect of different types of bone grafts, effect of pharyngoplasty in place at the time of osteotomy, and effectiveness of various methods of internal fixation. Tracings of preoperative and serial postoperative lateral cephalograms were digitized to calculate horizontal and vertical maxillary changes. No significant differences in outcome was seen between patients who had maxillary surgery alone and those who had operations on both jaws, nor did the outcome vary significantly with the type of autogenous bone graft used or the segmentalization of the Le Fort osteotomy. Mean "effective" advancement was greater immediately and 2 years after surgery in those patients who did not have a pharyngoplasty in place before the operation. Advancement also was greater immediately and after 2 years in the miniplate fixation group than in patients with direct-wire fixation. Mean downward (vertical) displacement was 2.6 mm with a relapse of 1.4 mm after 2 years. Amounts of relapse and of advancement or displacement did not correlate significantly.     

Subthalamic Nucleus Deep Brain Stimulation Modulate Catecholamine Levels with Significant Relations to Clinical Outcome after Surgery in Patients with Parkinson’s Disease

Aims

Although subthalamic nucleus deep brain stimulation (STN-DBS) is effective in patients with advanced Parkinson’s disease (PD), its physiological mechanisms remain unclear. Because STN-DBS is effective in patients with PD whose motor symptoms are dramatically alleviated by L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, the higher preoperative catecholamine levels might be related to the better clinical outcome after surgery. We aimed to examine the correlation between the preoperative catecholamine levels and postoperative clinical outcome after subthalamic nucleus deep brain stimulation. The effectiveness of STN-DBS in the patient who responded well to dopaminergic medication suggest the causal link between the dopaminergic system and STN-DBS. We also examined how catecholamine levels were modulated after subthalamic stimulation.

Methods

In total 25 patients with PD were enrolled (Mean age 66.2 ± 6.7 years, mean disease duration 11.6 ± 3.7 years). Mean levodopa equivalent doses were 1032 ± 34.6 mg before surgery. Cerebrospinal fluid and plasma catecholamine levels were measured an hour after oral administration of antiparkinsonian drugs before surgery. The mean Unified Parkinson’s Disease Rating Scale scores (UPDRS) and the Parkinson’s disease Questionnaire-39 (PDQ-39) were obtained before and after surgery. Of the 25 patients, postoperative cerebrospinal fluid and plasma were collected an hour after oral administration of antiparkinsonian drugs during on stimulation at follow up in 11 patients.

Results

Mean levodopa equivalent doses significantly decreased after surgery with improvement in motor functions and quality of life. The preoperative catecholamine levels had basically negative correlations with postoperative motor scores and quality of life, suggesting that higher preoperative catecholamine levels were related to better outcome after STN-DBS. The preoperative plasma levels of L-DOPA had significantly negative correlations with postoperative UPDRS- III score in off phase three months after STN-DBS. The preoperative cerebrospinal fluid (CSF) 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxytryptamine (5-HT) levels had significantly negative correlations with postoperative UPDRS- III score in off phase one year after STN-DBS and the preoperative CSF homovanilic acid (HVA) levels had significant negative correlations with postoperative UPDRS- III score in on phase three months after STN-DBS. In PDQ-39 SI (summary index), preoperative plasma dopamine (DA) level had significantly negative correlations with postoperative PDQ-39 SI one year after STN-DBS suggesting that higher preoperative plasma DA level resulted in better quality of life (QOL) one year after STN-DBS. The stepwise multiple linear regression study revealed that higher preoperative plasma HVA levels had negative influence on the postoperative motor symptoms (i.e., increase in the score of UPDRS), whereas higher preoperative CSF L-DOPA levels had positive influence on the postoperative motor symptoms and QOL (decrease in the score of UPDRS and PDQ-39 SI) The catecholamine levels were not significantly reduced postoperatively in 11 patients despite the significant reduction in levodopa equivalent doses. Unexpectedly, CSF HVA levels significantly increased from 0.00089±0.0003 ng/μl to 0.002±0.0008 ng/μl after STN-DBS.

Conclusion

The preoperative catecholamine levels might affect the postoperative motor symptoms and quality of life. The catecholamine levels were not significantly reduced postoperatively despite the significant reduction in levodopa equivalent doses.     

Sagittal craniosynostosis outcome assessment for two methods and timings of intervention.

A retrospective quantitative analysis of 40 infants who underwent surgery for sagittal craniosynostosis was conducted to determine whether any difference in outcome, with respect to cranial index (cranial width/cranial length x 100), could be associated with either the age at surgery or the extent of the operation. Children < or = 13 months old at surgery and for whom there were archived computed tomography digital data preoperatively, perioperatively, and 1 year postoperatively were studied. For statistical analysis, the operation was classified as either extended strip craniectomy or subtotal calvarectomy, and the age at operation was either < or = 4 months or > 4 months. Twenty-eight patients underwent extended strip craniectomy at a mean age of 5.1 months. Their mean cranial index preoperatively was 67 versus 71 at 1 year postoperatively (p < 0.0001). Of extended strip craniectomy patients, 15 were operated on at age < or = 4 months (mean = 2.9 months) and 13 at age > 4 months (mean = 7.6 months). Mean cranial indices for age at operation groups did not achieve age-appropriate normal range values 1 year postoperatively for either group, and there was no significant difference between the mean percentages of improvement achieved (p = 0.143). Twelve patients underwent subtotal calvarectomy at a mean age of 5.2 months. Their mean cranial index preoperatively was 66 versus 74 at 1 year postoperatively (p < 0.0001). The mean cranial index in this group reached age-appropriate normal range values 1 year postoperatively. The percentage improvement in cranial index 1 year after subtotal calvarectomy was greater than after extended strip craniectomy (p = 0.003). Extended strip craniectomy for sagittal craniosynostosis does not achieve normal cranial width:length proportions, even when performed before 4 months of age. Subtotal calvarectomy for sagittal craniosynostosis does achieve normal cranial width:length proportions in the majority of the children, at least when performed within the first 13 months of life.     

Partial trisomy 20q in a newborn with dextrocardia

A female newborn is reported with dextrocardia and a partial trisomy 20q, derived from a t(2;20) paternal translocation. The most discriminating findings of the condition include brachycephaly, bulging forehead, deep set eyes, short nose, large ears, dimpled chin, short neck and a heart defect. Previously reported patients with this rare chromosomal anomaly are reviewed.     

Activating Somatic FGFR2 Mutations in Breast Cancer

It is known that FGFR2 gene variations confer a risk for breast cancer. FGFR2 and FGF10, the main ligand of FGFR2, are both overexpressed in 5–10% of breast tumors. In our study, we sequenced the most important coding regions of FGFR2 in somatic tumor tissue of 140 sporadic breast cancer patients and performed MLPA analysis to detect copy number variations in FGFR2 and FGF10. We identified one somatic heterozygous missense mutation, p.K660N (c.1980G>C), within the tyrosine kinase domain of FGFR2 in tumor tissue of a sporadic breast cancer patient, which is likely mediated by the FGFR2-IIIb isoform. The presence of wild type and mutated alleles in equal quantities suggests that the mutation has driven clonal amplification of mutant cells. We have analyzed the tyrosine kinase activity of p.K660N and another recently described somatic breast cancer mutation in FGFR2, p.R203C, after expression in HEK293 cells and demonstrated that the intrinsic tyrosine kinase activity of both mutant proteins is strongly increased resulting in elevated phosphorylation and activity of downstream effectors. To our knowledge, this is the first report of functional analysis of somatic breast cancer mutations in FGFR2 providing evidence for the activating nature of FGFR2-mediated signalling in the pathogenesis of breast cancer.     

老年患者术后急性精神障碍临床观察与护理体会

目的：观察老年术后急性精神障碍发生的相关原因并总结护理要点。方法：回顾分析老年术后发生急性精神障碍的相关因素包括手术与麻醉时间、术前合并症和术后并发症等。结果：术后急性精神障碍与多种因素相关。与全身麻醉以及术后不良的环境因素密切相关,其他原因包括年龄、术前合并症以及术后并发症的发生等。术后必要的药物治疗以及术后的心理护理是护理工作的关键,患者信赖的医护人员以及亲友的安慰交流有防治效果。结论：老年病人术后精神障碍的发生对围手术期病人的治疗康复具有一定的负面影响,应当引起医护人员的重视并采取有效防治对策。     

FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features

Mutations in multiple oncogenes including KRAS, CTNNB1, PIK3CA and FGFR2 have been identified in endometrial cancer. The aim of this study was to provide insight into the clinicopathological features associated with patterns of mutation in these genes, a necessary step in planning targeted therapies for endometrial cancer. 466 endometrioid endometrial tumors were tested for mutations in FGFR2, KRAS, CTNNB1, and PIK3CA. The relationships between mutation status, tumor microsatellite instability (MSI) and clinicopathological features including overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan-Meier survival analysis and Cox proportional hazard models. Mutations were identified in FGFR2 (48/466); KRAS (87/464); CTNNB1 (88/454) and PIK3CA (104/464). KRAS and FGFR2 mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors. KRAS and FGFR2 occurred in a near mutually exclusive pattern (p = 0.05) and, surprisingly, mutations in KRAS and CTNNB1 also occurred in a near mutually exclusive pattern (p = 0.0002). Multivariate analysis revealed that mutation in KRAS and FGFR2 showed a trend (p = 0.06) towards longer and shorter DFS, respectively. In the 386 patients with early stage disease (stage I and II), FGFR2 mutation was significantly associated with shorter DFS (HR = 3.24; 95% confidence interval, CI, 1.35-7.77; p = 0.008) and OS (HR = 2.00; 95% CI 1.09-3.65; p = 0.025) and KRAS was associated with longer DFS (HR = 0.23; 95% CI 0.05-0.97; p = 0.045). In conclusion, although KRAS and FGFR2 mutations share similar activation of the MAPK pathway, our data suggest very different roles in tumor biology. This has implications for the implementation of anti-FGFR or anti-MEK biologic therapies.     

Pre- and postoperative accommodative convergence/accommodation (AC/A) ratio: preliminary study of computer-assisted analyses

A group of 15 patients who underwent bilateral medial rectus muscle recession for esodeviation were analyzed for factors most closely correlated with the outcome. The data evaluated included age of onset of strabismus, refractive error, year of surgery, age of surgery, sex, preoperative esodeviation, and clinical assessment of preoperative heterophoria. Linear regression analysis was used to evaluate the relationships of these parameters. Computer-assisted logistic regression analysis and discriminant analysis were used to asses predictive variables for a postoperative increase in the AC/A ratio.     

Association of a P2RX7 gene missense variant with brachycephalic dog breeds

Missense variants are associated with various phenotypic traits and disorders in dogs. The canine P2RX7 gene, coding the ATP-gated P2X7 receptor ion channel, contains four known missense variants. The current study aimed to examine the presence of these variants in a random sample of pedigree and mixed-pedigree dogs. Exons 3, 8, 11 and 13 of the P2RX7 gene, encoding these four respective variants, in 65 dogs were assessed by Sanger sequencing and combined with existing sequencing data from another 69 dogs. The distribution of these variants was then evaluated in all 134 dogs combined and separately within individual breeds including 35 different pure breeds. The rs23314713 (p.Phe103Leu) and rs23315462 (p.Pro452Ser) variants were present in 47 and 40% of all dogs studied respectively, with the rs23314713 variant associated with brachycephalic breeds. Among pedigree dogs, the rs23314713 and rs23315462 variants were associated with brachycephalic and non-brachycephalic breeds respectively. The rs851148233 (p.Arg270Cys) and rs850760787 (p.Arg365Gln) variants were present only in dogs of Cocker Spaniel and Labrador Retriever pedigrees respectively. No other missense variants were found in exons 3, 8, 11 and 13 of the P2RX7 gene within the dogs. In conclusion, the rs23314713 and rs23315462 missense variants of the P2RX7 gene are present in a large proportion of dogs, with the rs23314713 variant associated with a number of brachycephalic breeds. However, the association of this variant with dogs of bulldog ancestry, not brachycephaly per se, cannot be excluded.     

Renal function outcomes after nephrectomy for kidney cancer in elderly patients

The kidneys are organs with multiple functions and essential to maintain life. Ablative procedures, such as nephrectomy, diminish nephron mass and can have a potentially negative impact on renal function. We investigated renal function outcome in patients who underwent nephrectomy for renal cell cancer with special emphasize on elderly patients. Data from 104 patients who underwent nephrectomy for kidney cancer in the Department of Urology, University Hospital Rijeka from January 2005 to December 2010 were retrospectively analyzed. All patients had a normal concentration of serum creatinine and a normal contralateral kidney before surgery. Renal function, as estimated by the glomerular filtration rate (eGFR), was determined before and after nephrectomy using the abbreviated Modification of Diet in Renal Disease equation. We compared the eGFR before and after nephrectomy in the patients of different age. The mean preoperative eGFR was 75.2 mL/min, and the mean postoperative eGFR was 52.7 mL/min (p < 0.0001). In the group of patients > or = 65 years old, the mean preoperative GFR was 69.2 mL/min, and the mean postoperative eGFR was 47.4 mL/min (p < 0.0001). Our data indicate that the eGFR significantly decreased after nephrectomy for kidney cancer. In elderly patients, diminished renal function following nephrectomy was more prominent.