Morphological variability in unrepaired bilateral clefts with and without cleft palate evaluated with geometric morphometrics.

In subjects with orofacial clefts, there is an unresolved controversy on the effect of congenital maxillary growth deficiency vs. the effect of surgical intervention on the outcome of treatment. Intrinsic growth impairment in subjects with orofacial clefts can be studied by comparing facial morphology of subjects with untreated cleft and unaffected individuals of the same ethnic background. Bilateral cleft lip and palate is the most severe and least prevalent form of the orofacial cleft. The aim of this study was to compare facial morphology in subjects with unrepaired complete bilateral clefts and unaffected controls using geometric morphometrics. Lateral cephalograms of 39 Indonesian subjects with unrepaired bilateral complete cleft lip and alveolus (mean age: 24 years), or unrepaired bilateral complete cleft lip, alveolus, and palate (mean age: 20.6 years) and 50 age and ethnically matched controls without a cleft (25 males, 25 females, mean age: 21.2 years) were digitized and traced and shape variability was explored using principal component analysis, while differences between groups and genders were evaluated with canonical variate analysis. Individuals with clefts had a more pronounced premaxilla than controls. Principal component analysis showed that facial variation in subjects with clefts occurred in the anteroposterior direction, whereas in controls it was mostly in the vertical direction. Regression analysis with group, sex, and age as covariates and principal components from 1 to 6 as dependent variables demonstrated a very limited effect of the covariates on the facial shape variability (only 11.6% of the variability was explained by the model). Differences between cleft and non-cleft subjects in the direction of facial variability suggest that individuals with bilateral clefts can have an intrinsic growth impairment affecting facial morphology later in life.

The Slavcleft: A three-center study of the outcome of treatment of cleft lip and palate. Part 2: Dental arch relationships.

PURPOSE: Our aim was to evaluate the dental arch relationship in a preadolescent Slavic population with unilateral cleft lip and palate (UCLP) by using the Goslon Yardstick. MATERIALS AND METHODS: Patients treated in Warsaw, Poland (n = 32), Prague, Czech Republic (n = 33) and Bratislava, Slovakia (n = 30) were included in this retrospective study. Each cleft center used a unique surgical protocol. Three raters scored blindly the dental arch relationship on plaster models. Intra- and inter-rater agreement were assessed with kappa statistics, and differences between the groups were evaluated with one-way analysis of variance. Intra-rater agreement was very good (k > 0.825), while inter-rater agreement was either good or very good (kappa >0.703). RESULTS: We found that patients treated in Warsaw showed a more favorable dental arch relationship (Goslon score = 2.58, SD = 0.77) than patients treated in Prague (Goslon score = 3.21, SD = 1.04). Patients treated in Bratislava showed an intermediate Goslon score (3.07; SD = 0.99). CONCLUSION: This study showed that the dental arch relationships in patients treated in Warsaw with a one-stage repair were more favorable than in patients treated in Prague and Bratislava with a two-stage protocol and comparable to the best results obtained in the Eurocleft and Americleft studies.

Current Approaches in the Development of Molecular and Pharmacological Therapies in Craniosynostosis Utilizing Animal Models.

The development of the craniofacial skeleton is a spatial and temporal process where cranial sutures play a role in the regulation of morphogenesis and growth. Disruption of these cellular and molecular interactions may lead to craniosynostosis, the premature obliteration of one or more cranial sutures, yielding skull growth restriction and malformation perpendicular to the affected suture. Facial deformity and various functional CNS anomalies are other frequent complications. Cranial vault expansion and reconstructive surgery remain the mainstay of treatment but pose an elevated risk of morbidity for the infant. While the etiology of nonsyndromic craniosynostosis remains to be deciphered, gain-of-function mutations in FGFR1-3 and TWIST1 were found to be responsible for more than 3/4 of the most commonly encountered craniofacial syndromes. Animal models have been invaluable to further dissect the role of genes within the cranial sutures and for the development of alternative nonsurgical treatment strategies. In this review, we will present various molecular and pharmacological approaches for the treatment of craniosynostosis that have been tested using in vitro and in vivo assays as well as discuss their potential application in humans focusing on the case of tyrosine kinase inhibitors.

Mandibular symphyseal distraction osteogenesis: 20 years of experience treating transverse deficiencies with an internal hybrid device.

INTRODUCTION: Transverse mandibular deficiency has been traditionally managed by orthodontic compensation. However, without resolving the underlying skeletal hypoplasia it leads to high relapse rates. Few studies have reviewed the long-term experience and potential complications of mandibular symphyseal distraction osteogenesis (MSDO) as an alternative treatment method. MATERIALS AND METHOD: A retrospective review of 20 patients (range: 4-19 years; mean: 11.9 years) treated with a hybrid MSDO device over the period of 1996-2017 was conducted. Epidemiological data, medical and dental history as well as photographic and cephalometric analyses were carried out. Furthermore, pre-operative and long-term post-operative status including dental occlusion and tooth-jaw discrepancies were recorded. RESULTS: The distraction amount ranged from 3 mm to 15 mm (mean: 10 mm) with an average distraction period of 30.9 days. In long-term follow-up (mean: 7.3 years), 14 patients presented a class I and 6 patients presented a class II relationship. Correction of overjet, tooth jaw discrepancy and arch length discrepancy were obtained in 18, 20 and 17 cases respectively. A device malfunction was experienced in 6 patients. CONCLUSION: Mandibular widening using a hybrid MSDO device can be efficiently and safely performed in a paediatric population. Further studies confirming our results and analysing facial aesthetic outcomes are warranted.

Secondary alveolar bone grafting in cleft lip and palate: A comparative analysis of donor site morbidity in different age groups.

INTRODUCTION: There is no consensus regarding the optimal timing for secondary alveolar bone grafting for clefts defects. We aimed to investigate the potential correlation between the age of patients during surgery, donor site symptoms, surgical time and hospitalization following this procedure. MATERIAL AND METHODS: The outcome of 195 consecutive alveolar bone grafting procedures among different age groups (mean: 7.1 years; range 1.8-40.5) was retrospectively assessed based on a chart review and purpose-prepared report forms. The association between age, gender and hospitalization following bone harvesting was tested by Spearman rank correlation, while relationships (i.e. between age and pain) were evaluated by logistic regression. RESULTS: The most frequent donor site complaints included: pain equal to or exceeding that of the recipient site (93%) and gait disturbances (92.5%) immediately after the procedure. Chronic complaints included: iliac contour alteration (40.1%), unsightly scar (23%) and recurring discomfort (2.1%). Statistical analysis showed no correlation between donor site symptoms, their duration or hospitalization time following surgery at different ages, except a higher incidence of significant pain immediately after bone harvesting in older females (r = 0.268; p = 0.030). CONCLUSION: Alveolar bone grafting at an earlier age does not increase donor site symptoms, surgical duration or hospitalization following surgery.

Early versus late alveolar bone grafting in unilateral cleft lip and palate: Dental arch relationships in pre-adolescent patients.

OBJECTIVE: To evaluate the dental arch relationship in preadolescent children with complete unilateral cleft lip and palate after early secondary alveolar bone grafting (E-ABG) by comparing to late bone grafting (L-ABG). MATERIAL AND METHODS: Two raters blindly assessed the dental arch relationship with the modified Huddart-Bodenham (HB) Index for 2 groups: E-ABG group (36 children, mean age 9.6 years) and L-ABG group (56 children, mean age 11.1 years). The groups differed with respect to age at which alveolar bone grafting was performed: between 1.4 and 4.1 years (mean 2.2 years, E-ABG group) and after 8 years (L-ABG group). T-test was run to compare scores between 2 groups. Regression analysis was carried out to evaluate gender, age at cleft repair, age at ABG, and age at assessment with the HB index. RESULTS: The overall HB scores were -6.77 and -4.25 in the E-ABG and L-ABG groups, respectively (p = 0.025). Regression analysis showed that only the age at cleft repair influenced the HB scores. CONCLUSION: ABG carried out between 2 and 4 years of age does not seem to negatively affect the dental arch relationship at the age of 10 years in comparison to L-ABG.

Current concepts in cleft care: A multicenter analysis.

The current surgical techniques used in cleft repair are well established, but different centers use different approaches. To determine the best treatment for patients, a multi-center comparative study is required. In this study, we surveyed all craniofacial departments registered with the German Society of Maxillofacial Surgery to determine which cleft repair techniques are currently in use. Our findings revealed much variation in cleft repair between different centers. Although most centers did use a two-stage approach, the operative techniques and timing of lip and palate closure were different in every center. This shows that a retrospective comparative analysis of patient outcome between the participating centers is not possible and illustrates the need for prospective comparative studies to establish the optimal technique for reconstructive cleft surgery.

Melanotic neuroectodermal tumor of infancy (MNTI) of the head and neck: A French multicenter study.

OBJECTIVES: Melanotic neuroectodermal tumor of infancy (MNTI) of the head and neck is a rare entity with uncertain clinical behavior. Radical surgical resection is the current recommended treatment, however this can cause severe aesthetic and functional sequelae. The aim of this study was to clinically characterize MNTIs and to stratify risk factors that may influence locoregional recurrence. METHODS: A retrospective multicenter study, including 11 patients from eight centers with a confirmed diagnosis of MNTI, was conducted. Epidemiological, clinical, radiological, pathological, and immunohistochemical examinations were reviewed. A statistical analysis using a t-test was conducted to calculate parameters correlating with tumor recurrence. RESULTS: MNTIs mainly occurred in the maxilla, with a mean age at diagnosis of 3.18 months (range: 0-6 months). Primary surgery was performed on 10 patients, with a clear margin resection on two patients. Overall recurrence rate was 27% with a survival of 100% at time of follow-up. No statistical correlation between recurrence rate, age at diagnosis, localization, resection margins, and pathological and immunohistochemical characteristics could be established. CONCLUSION: In our study, locoregional tumor recurrence did not seem to correlate with resection margins, so a conservative surgical approach may need to be considered to avoid functional and aesthetic sequelae.

Phenotypic spectrum of Tessier facial cleft number 5.

INTRODUCTION: Craniofacial clefts belong to the most disfiguring and rare congenital malformations of the face and among these, orbito-facial clefts constitute approximately 0.22 % of the cases with Tessier cleft number 5 being the least common. Our aim was to define the phenotypic spectrum for this subgroup to improve clinical management. METHODS: Our study group consisted of four patients which were treated at two different cleft centers. Retrospective chart review and anatomical analysis were conducted for each patient based on clinical evaluation and imaging studies. Morphological anomalies including soft tissue, bone and oral components were recorded. RESULTS: Based on our analysis and literature review, we could define two subtypes of Tessier facial cleft number 5. (1) Medial clefts are the more severe subtype, creating a significant soft tissue and bone defect that runs vertically, through the eyelid, infraorbital rim, maxillary sinus and cheek. They have the poorer esthetic and functional prognosis, due to orbital dystopia and absence of lower eyelid. (2) Lateral clefts are a less severe subtype characterized by the presence of a vertical furrow of the cheek running laterally to the maxillary sinus. CONCLUSIONS: We identified two subtypes of facial cleft number 5 which require an individualized surgical management.

The Slav-cleft: A three-center study of the outcome of treatment of cleft lip and palate. Part 1: Craniofacial morphology.

Results of a comparison of the outcomes of treatment of cleft lip and palate can be affected by growth characteristics of populations from which subjects with the clefts are derived. Moreover, conventional cephalometric techniques used in cleft studies for analysis of facial morphology provide only a partial description of shape and are confounded by biases regarding the reference structures. In this retrospective comparison, craniofacial morphology of preadolescent patients with unilateral cleft lip and palate treated in Warsaw (n = 35, age = 10.6 years, SD = 1.2), Prague (n = 38, age = 11.6 years, SD = 1.4), and Bratislava (n = 26, age = 10.5 years, SD = 1.6) were evaluated on cephalograms with the cephalometric method used in the Eurocleft study and geometric morphometrics. We found that patients treated in Warsaw showed slightly more favorable outcomes than in Prague and Bratislava. The differences were related primarily to the position of maxillary alveolar process, cranial base, mandibular angle, and soft tissues. Although no association between a component of treatment protocol and the outcome was found, it is possible that organizational factors such as participation of high-volume, experienced surgeons contributed to these results.

Harvey Cushing's Contributions to Plastic Surgery: Bilateral Cleft Lip Repair.

Harvey Cushing has been deemed by many as the neurosurgeon of the 20th century. Cushing's unknown contributions to the field of plastic and reconstructive surgery were only recently reported. Further review of his teaching and operative records, brought from Johns Hopkins to Yale University, revealed an unpublished case of bilateral cleft lip repair that he performed. In this article, we present in detail this comprehensive case and describe, with the help of his personal teaching notes and illustrations, how Cushing combined methods from world-renowned surgeons to approach bilateral cleft lip deformities.

Mutations in the interleukin receptor IL11RA cause autosomal recessive Crouzon-like craniosynostosis.

We have characterized a novel autosomal recessive Crouzon-like craniosynostosis syndrome in a 12-affected member family from Antakya, Turkey, the presenting features of which include: multiple suture synostosis, midface hypoplasia, variable degree of exophthalmos, relative prognathism, a beaked nose, and conductive hearing loss. Homozygosity mapping followed by targeted next-generation sequencing identified a c.479+6T>G mutation in the interleukin 11 receptor alpha gene (IL11RA) on chromosome 9p21. This donor splice-site mutation leads to a high percentage of aberrant IL11RA mRNA transcripts in an affected individual and altered mRNA splicing determined by in vitro exon trapping. An extended IL11RA mutation screen was performed in a cohort of 79 patients with an initial clinical diagnosis of Crouzon syndrome, pansynostosis, or unclassified syndromic craniosynostosis. We identified mutations segregating with the disease in five families: a German patient of Turkish origin and a Turkish family with three affected sibs all of whom were homozygous for the previously identified IL11RA c.479+6T>G mutation; a family with pansynostosis with compound heterozygous missense mutations, p.Pro200Thr and p.Arg237Pro; and two further Turkish families with Crouzon-like syndrome carrying the homozygous nonsense mutations p.Tyr232* and p.Arg292*. Using transient coexpression in HEK293T and COS7 cells, we demonstrated dramatically reduced IL11-mediated STAT3 phosphorylation for all mutations. Immunofluorescence analysis of mouse Il11ra demonstrated specific protein expression in cranial mesenchyme which was localized around the coronal suture tips and in the lambdoidal suture. In situ hybridization analysis of adult zebrafish also detected zfil11ra expression in the coronal suture between the overlapping frontal and parietal plates. This study demonstrates that mutations in the IL11RA gene cause an autosomal recessive Crouzon-like craniosynostosis.

Craniosynostosis and multiple skeletal anomalies in humans and zebrafish result from a defect in the localized degradation of retinoic acid.

Excess exogenous retinoic acid (RA) has been well documented to have teratogenic effects in the limb and craniofacial skeleton. Malformations that have been observed in this context include craniosynostosis, a common developmental defect of the skull that occurs in 1 in 2500 individuals and results from premature fusion of the cranial sutures. Despite these observations, a physiological role for RA during suture formation has not been demonstrated. Here, we present evidence that genetically based alterations in RA signaling interfere with human development. We have identified human null and hypomorphic mutations in the gene encoding the RA-degrading enzyme CYP26B1 that lead to skeletal and craniofacial anomalies, including fusions of long bones, calvarial bone hypoplasia, and craniosynostosis. Analyses of murine embryos exposed to a chemical inhibitor of Cyp26 enzymes and zebrafish lines with mutations in cyp26b1 suggest that the endochondral bone fusions are due to unrestricted chondrogenesis at the presumptive sites of joint formation within cartilaginous templates, whereas craniosynostosis is induced by a defect in osteoblastic differentiation. Ultrastructural analysis, in situ expression studies, and in vitro quantitative RT-PCR experiments of cellular markers of osseous differentiation indicate that the most likely cause for these phenomena is aberrant osteoblast-osteocyte transitioning. This work reveals a physiological role for RA in partitioning skeletal elements and in the maintenance of cranial suture patency.

A mutation screen in patients with Kabuki syndrome.

Kabuki syndrome (KS) is one of the classical, clinically well-known multiple anomalies/mental retardation syndromes, mainly characterized by a very distinctive facial appearance in combination with additional clinical signs such as developmental delay, short stature, persistent fingerpads, and urogenital tract anomalies. In our study, we sequenced all 54 coding exons of the recently identified MLL2 gene in 34 patients with Kabuki syndrome. We identified 18 distinct mutations in 19 patients, 11 of 12 tested de novo. Mutations were located all over the gene and included three nonsense mutations, two splice-site mutations, six small deletions or insertions, and seven missense mutations. We compared frequencies of clinical symptoms in MLL2 mutation carriers versus non-carriers. MLL2 mutation carriers significantly more often presented with short stature and renal anomalies (p = 0.026 and 0.031, respectively), and in addition, MLL2 carriers obviously showed more frequently a typical facial gestalt (17/19) compared with non-carriers (9/15), although this result was not statistically significant (p = 0.1). Mutation-negative patients were subsequently tested for mutations in ten functional candidate genes (e.g. MLL, ASC2, ASH2L, and WDR5), but no convincing causative mutations could be found. Our results indicate that MLL2 is the major gene for Kabuki syndrome with a wide spectrum of de novo mutations and strongly suggest further genetic heterogeneity.