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Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition is caused by a common, recurring, gain-of-function mutation in FGFR3, the gene that encodes fibroblast growth factor receptor 3. This mutation leads to impaired endochondral ossification of the human skeleton. The clinical and radiographic hallmarks of achondroplasia make accurate diagnosis possible in most patients. However, marked variability exists in the clinical care pathways and protocols practised by clinicians who manage children and adults with this condition. A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process. The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide in order to optimize their clinical outcomes and quality of life. Achondroplasia is the most common skeletal dysplasia and is characterized by various lifelong clinical, functional and psychosocial challenges for affected individuals. This first International Consensus Statement on the care of children and adults with achondroplasia aims to facilitate the global standardization and improvement of achondroplasia clinical care.

BACKGROUND The medial and maxillary aspects of the upper lip originate at separate embryonic stages and therefore may experience different maternal exposure patterns which may affect methylation. Based on this hypothesis, we investigated the level of methylation of the methylene tetrahydrofolate reductase promoter gene (mMTHFR) in tissues from cleft lip, and mMTHFR levels by MTHFR c.677C > T genotype. We further investigated whether mMTHFR mitigates the effect of smoking on long interspersed nuclear element (LINE-1) methylation in these tissues. METHODS DNA extracted from medial and lateral tissues of 26 infants with nonsyndromic cleft lip with or without cleft palate (nsCL/P) was bisulfite converted and mMTHFR was measured on a pyrosequenser. LINE-1 methylation and MTHFR c.677C > T genotype data were obtained in our previous study. RESULTS There was no substantial difference in mMTHFR (p = .733) and LINE-1 (p = .148) between the two tissues. mMTHFR was not influenced by MTHFR c.677C > T genotype, but there was suggestive evidence that the difference was larger among infants exposed to maternal smoking compared to nonexposed. LINE-1 methylation differences were significant (p = .025) in infants born to nonsmoking mothers, but this was not apparent (p = .872) in infants born to mothers who smoked. Our Pearson's correlation analysis suggested a weak inverse association between mMTHFR and LINE-1 (r = -.179, p = .381). CONCLUSION Our preliminary observation of differences in patterns of mMTHFR levels in lip tissue suggests the interplay of gene and environment in the establishment of methylation in tissues at both sides of cleft lip. This requires investigation in a larger cohort, integrated with metabolic assessment.

OBJECTIVE A preliminary study to determine collagen fibril diameter (CF-ED) distribution on medial and lateral sides of cleft lip (CL). MATERIAL AND METHODS Tissue samples from medial and lateral sides of CL were fixed in 2.5% glutaraldehyde and 1% osmium tetroxide and embedded in Araldite CY212 resin for transmission electron microscopy. The analysis of CF-ED was performed using the ImageJ program. To characterize the packaging of collagen fibrils (CFs) in the two tissues, we estimated the collagen number density (CF-ND) and fibril-area-fraction (FAF). Differences in measurements across the two sides were calculated using Wilcoxon signed-rank test. RESULTS The CF-ED was statistically significantly (p

Introduction: The objective of this prospective study was to compare the difference in pain perception between treatment with aligners (AL) and fixed appliances (FA) in patients affected by cleft and craniofacial anomalies (CFA). Methods: The sample consisted of 100 syndromic caucasian patients affected by various CFA from 2 different hospitals. Fifty patients treated with AL were matched for sex, age, and CFA with a control sample of 50 patients treated with FA. A modification of the Mc Gill Pain Questionnaire was adapted to our needs. Results: Statistical differences were found. Aligners induced more tightness and tension than FA, while FA induced more pain descriptors and patients reported a higher intake of painkillers. Conclusions: The results of this study documented a higher pain perception with FA than with AL in patients affected by CFA. The higher sensitivity to pain in cleft and craniofacial patients with fixed treatment could be related to their higher prior sensitization, given the past surgeries and orthodontic treatments. Thus, this study might suggest that Invisalign treatment might be a further interesting treatment option for patients with cleft in order to reduce their burden of orthodontic pain.

Introduction Cleft lip and palate (CLP) surgery interferes with maxillary growth and contributes to transversal and sagittal growth impairment. Our retrospective descriptive study aimed to evaluate maxillary bone shape in a homogenous unilateral CLP patient group using geometric morphometrics based on CT-scan data. Material and methods We included all patients with available CT-scans at the end of pubertal growth and operated on at Smile House of Milan, according to the standard protocol, involving two surgical steps: (1) primary closure of the lip and soft palate at 6 months of age and (2) early secondary gingivoalveoloplasty (GAP) associated with hard palate repair at 18–36 months. Shape differences between CLP and an age-matched control group were characterized using geometric morphometrics based on 15 3D landmarks. Results We included 16 unilateral CLP patients and 20 age-matched controls. Principal component and canonical variate analyses showed that the maxillary shape in CLP was significantly different from controls but that this difference was limited. Linear and angular measurements confirmed these differences. Conclusion Early secondary GAP results in satisfactory maxillary shape, with significant but limited differences relative to controls.

Objective: To investigate the influence of MTHFR c.677C>T genotype on LINE-1 methylation in lateral and medial tissues from cleft lip (CL). Methods: Forty-five consecutive non-syndromic cleft lip with or without cleft palate (nsCL/P) cases were included in the study. Genomic DNA was extracted from tissues at both sides of cleft lip, and LINE-1 methylation was detected by bisulfite conversion and pyrosequencing. MTHFR c.677C>T genotyping was carried out using the TaqMan genotyping assay. Results: LINE-1 methylation level was significantly higher on medial side of cleft lip compared with lateral side (p = 0.001). This difference was not significantly influenced by the case's sex or cleft type. However, MTHFR c.677C>T genotyping revealed that the difference in LINE-1 methylation across cleft lip was restricted to carriers of C allele of MTHFR c.677C>T and was not apparent in TT homozygous cases (p = 0.027). Conclusion: This integrated analysis supports the previous finding of differences in DNA methylation across the two sides of cleft lip and further suggests a possible role of MTHFR c.677C>T genotype in establishing this difference.

The aim of this study was to evaluate any differences between the craniofacial growth of unilateral cleft lip and palate (UCLP) patients who underwent surgery in the Milan CLP centre with those from the Oslo CLP centre at 5 and 10 years of age. The Milan sample comprised 88 UCLP patients (60 males, 28 females) at 5 years of age and 26 patients (17 males, 9 females) at 10 years of age all operated on by the same surgeon. The Oslo sample consisted of 48 UCLP patients (26 males, 22 females) aged 5 years and 29 patients (20 males, 9 females) aged 10 years treated by four different surgeons. Lateral cephalometric radiographs obtained for both samples were analysed and angular measurements and ratios were calculated both for the hard and soft tissues. Statistical analysis was undertaken with an unpaired t-test. At 5 years of age, there were neither sagittal nor vertical hard tissue differences between the two groups. With regard to the soft tissues, only the naso-labial angle showed a statistically significant difference (Milan greater than Oslo by 5 degrees, P0.01). At 10 years of age, both SNA and ANB differences were larger in the Oslo group than in the Milan group,2.6 degrees, P0.01 and2.9 degrees, P0.001, respectively. At 5 years of age, the Milan UCLP sample had the same maxillary protrusion as the Oslo group, while at 10 years of age, the Milan sample were slightly less protruded than the Oslo group.

Background: Midface distraction osteogenesis (DO) in craniofacial synostosis (CFS) patients has been described by several authors. However, very few cephalometric and computed tomography (CT) long-term follow-up studies are available. Method: A total of 40 consecutive patients affected by CFS subjected to Le Fort III and rigid external distraction (RED) were examined. All patients had pre-DO cephalometric records, immediately post-DO and 6-12 months post-DO. Twenty-seven patients had mid-term records (3 years post-DO) and 20 patients had long-term records (5-10 years post-DO). Fourteen patients had CT data within 1-year of DO, while 10 patients had long-term CT data (range 5-9 years). Results: Excellent post-surgical stability was recorded. Short- and long-term CT data demonstrated excellent ossification at the osteotomy sites post-DO. In the growing patients, surface resorption in the zygomatic-temporal and in the subspinal area (p < 0.05) was observed in the long-term follow-up, as well as a mild increment of the corrected exorbitism (p < 0.05), as only appositional and no sutural growth occurs post Le Fort III, whereby orbital volume does not increase after surgery. Conclusion: Significant advancement of the midface can be achieved and maintained through Le Fort III and RED. In the long term, in growing patients, in general a class III malocclusion does not re-occur, but physiological remodelling processes at the maxillary-zygomatic level, not coupled with sutural growth, tend to mildly re-express the original midfacial phenotype and the exorbitism. © 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Introduction Long-term results after orthopedic or surgical treatment of hemifacial microsomia (HFM) have shown a tendency toward recurrence of the facial asymmetry. However, the literature contains a number of successful case reports that show surprising changes in the morphology of the condyles. In addition, patients with similar mandibular asymmetries, treated early with surgery, have excellent long-term follow-ups, especially those who have little or no soft-tissue involvement, but only severe mandibular ramal deformities. The phenotypes of these cases are unexpectedly similar, with a consistent collapse of the condyle against the coronoid and a deep sigmoid notch. The objectives of this article were to help distinguish true HFM from this peculiar type of hemimandibular asymmetry morphologically and to quantify their differences before treatement and in the long term. Methods Panoramic radiographs taken at pretreatment and the long-term follow-up of 9 patients with hemimandibular hypoplasia, characterized by the collapse of the condyle against the coronoid, were compared with those of 8 patients with severe type I and type II HFM; these records were collected before and at least 10 years after distraction osteogenesis. Results Ratios and angular measurements before and after treatment differed significantly between the 2 groups. Conclusions Perhaps these patients were misdiagnosed and actually had secondary injuries of the condyle, which have a normal functional matrix. Therefore, with growth and functional stimulation, they would tend to grow toward the original symmetry. To make a differential diagnosis between true HFM and this peculiar type of hemimandibular hypoplasia, the collaboration between not only orthodontists and surgeons, but also geneticists and dysmorphologists, is of great importance because of the different prognoses.

The Milan surgical protocol from 1988 has included repair of lip, nose, and soft palate at 6-9 months of age, and closure of the hard palate and alveolus with an early secondary gingivoalveoloplasty at 18-36 months. The goal of this study was to evaluate the long-term maxillary growth in patients with unilateral cleft lip and palate (UCLP) who had had the early secondary gingivoalveoloplasty, compared with the growth in a sample treated before 1988, by the same surgeon, with a surgical protocol that differed only by the method and the timing of alveolar closure. In the second group they were repaired by secondary bone grafting. The samples consisted of lateral cephalograms of the UCLP early secondary gingivoalveoloplasty sample (15 patients with a mean age of 18 (1.2) years) and of the UCLP bone graft sample (10 patients with a mean age of 19 (1.1) years). The early secondary gingivoalveoloplasty patients showed that maxillary growth was inhibited compared with the secondary bone graft group. Although the early secondary gingivoalveoloplasty allowed for early repair of the alveolus together with palatal repair, eliminating the need for secondary bone grafting, it seemed to have an inhibiting influence on maxillary growth that increased the need for Le Fort I osteotomies. Even with a Le Fort I osteotomy, the early secondary gingivoalveoloplasty allows the total number of operations to be kept down to three, as in most European protocols.

Objective: To compare the short- and long-term craniofacial growth of patients operated with the Milan protocol to those operated with the Oslo protocol. Design: The Milan sample included 88 patients with unilateral cleft lip and palate (UCLP) at 5 years, 26 at 10 years, and 23 at the end of growth. The Oslo samples included 48 UCLP patients at 5 years, 29 at 10, and 23 at growth completion. Lateral cephalograms were used for comparison. An unpaired t test was run for the 5- and 10-year-old samples. The samples long term were matched for age and sex, and a paired t test was run. Results: There was no significant cephalometric difference in the maxillary prominence at 5 years, a mild but significant difference at 10 years, and again no difference at the end of growth. Nevertheless, at an older age, the need for orthognathic surgery was larger in the Milan sample (26%) than in the Oslo sample (13%). Conclusion: Although no statistically significant differences in the cephalometric measurements were found long term, the need for orthognathic surgery was clinically judged to be larger in the Milan sample. On the other hand, although the Milan protocol seemed to require more final jaw surgery, only the cases that needed an additional orthognathic procedure in the Milan group will undertake a third surgical step, while the Oslo protocol included three surgical steps for all the patients.

No true consensus exists regarding the causes of maxillary growth restriction in cleft lip and palate patients. The aim of this study was to evaluate a simplified method to identify the causes of this growth impairment. We analyzed a sample of 82 consecutively treated 5-year-old patients with unilateral complete cleft lip and palate, operated on by the same surgeon (R.B.). Multiple cephalometric measurements of the sample revealed a wide distribution of maxillary growth values. We selected Sella-Nasion A point angle (SNA) as a value describing maxillary position, and we arbitrarily isolated 2 "extreme" groups of patients: the 20 patients with the highest SNA were called "good growers" (group A), and the 20 patients with the lowest SNA were called "poor growers" (group B). Parameters investigated to search for different influencing factors within the groups were initial cast measurements, timing of lip and of gingivoalveoloplasty/palatal surgery, presence of lateral incisors, and family history of maxillary hypoplasia. Statistical differences were investigated with an independent-samples t-test. The 2 extreme groups had a significant difference (P < 0.01) in SNA and in lip protrusion relative to true vertical line. Cranial base angle was larger in group A. Timing of lip surgery in group B was earlier than in group A, but only close to significance. Timing of gingivoalveoloplasty did not differ. In group A, the permanent lateral incisor was missing in 20% of the patients; whereas in group B, it was missing in 82% of the patients (P < 0.01). Selecting cleft lip and palate population with different growth pattern might help in isolating the factors responsible for maxillary growth impairment. Congenitally missing laterals that could indicate inherent tissue hypoplasia seems to be the most important factor.

Objective:To evaluate the dental characteristics of patients subjected to a protocol that included early secondary gingivoalveoloplasty (ESGAP).Design:Panoramic radiographs of 87 patients with unilateral cleft lip and palate (UCLP) and 29 with bilateral cleft lip and palate (BCLP) were evaluated. Missing and supernumerary teeth were also quantified on the cleft and noncleft side and in the maxilla and mandible. Crown and root malformations and tooth rotations were quantified. A subsample in permanent dentition was extrapolated to analyze canine eruption patterns.Results:A total of 48.8% of the UCLP patients presented with missing permanent lateral incisors in the cleft area and 6.1% contralaterally. A total of 4.9% presented with missing second maxillary premolars on the cleft site and 1.2% contralaterally. A total of 7.3% presented with supernumerary lateral incisors, and 45% of the BCLP cleft sites presented with missing lateral incisors, while 25% of the cleft sites presented second maxillary premolars agenesis. Five percent of the cleft sites presented with supernumerary lateral incisors. Evaluation of the subsample in permanent dentition showed that 15.5% had a canine retention and 4.4% of the canines had to be surgically exposed. A significant association was observed between canine inclination and retention but not with absence of the lateral incisor.Conclusions:The frequency of dental anomalies in this sample was similar to other cleft populations. As surgical trauma has been suggested to damage forming teeth, the results of this study indicated that ESGAP has no detrimental influence on subsequent dental development.