Automated assessment of mandibular shape asymmetry in 3-dimensions.

INTRODUCTION: This study aimed to develop an automatic pipeline for analyzing mandibular shape asymmetry in 3-dimensions. METHODS: Forty patients with skeletal Class I pattern and 80 patients with skeletal Class III pattern were used. The mandible was automatically segmented from the cone-beam computed tomography images using a U-net deep learning network. A total of 17,415 uniformly sampled quasi-landmarks were automatically identified on the mandibular surface via a template mapping technique. After alignment with the robust Procrustes superimposition, the pointwise surface-to-surface distance between original and reflected mandibles was visualized in a color-coded map, indicating the location of asymmetry. The degree of overall mandibular asymmetry and the asymmetry of subskeletal units were scored using the root-mean-squared-error between the left and right sides. These asymmetry parameters were compared between the skeletal Class I and skeletal Class III groups. RESULTS: The mandible shape was significantly more asymmetrical in patients with skeletal Class III pattern with positional asymmetry. The condyles were identified as the most asymmetric region in all groups, followed by the coronoid process and the ramus. CONCLUSIONS: This automated approach to quantify mandibular shape asymmetry will facilitate high-throughput image processing for big data analysis. The spatially-dense landmarks allow for evaluating mandibular asymmetry over the entire surface, which overcomes the information loss inherent in conventional linear distance or angular measurements. Precise quantification of the asymmetry can provide important information for individualized diagnosis and treatment planning in orthodontics and orthognathic surgery.

Identification of a recurrent mosaic KRAS variant in brain tissue from an individual with nevus sebaceous syndrome.

Nevus sebaceous syndrome (NSS) is a rare, multisystem neurocutaneous disorder, characterized by a congenital nevus, and may include brain malformations such as hemimegalencephaly or focal cortical dysplasia, ocular, and skeletal features. It has been associated with several eponyms including Schimmelpenning and Jadassohn. The isolated skin lesion, nevus sebaceous, is associated with postzygotic variants in HRAS or KRAS in all individuals studied. The RAS proteins encode a family of GTPases that form part of the RAS/MAPK signaling pathway, which is critical for cell cycle regulation and differentiation during development. We studied an individual with nevus sebaceous syndrome with an extensive nevus sebaceous, epilepsy, intellectual disability, and hippocampal sclerosis without pathological evidence of a brain malformation. We used high-depth gene panel sequencing and droplet digital polymerase chain reaction (PCR) to detect and quantify RAS/MAPK gene variants in nevus sebaceous and temporal lobe tissue collected during plastic and epilepsy surgery, respectively. A mosaic KRAS c.34G > T; p.(Gly12Cys) variant, also known as G12C, was detected in nevus sebaceous tissue at 25% variant allele fraction (VAF), at the residue most commonly substituted in KRAS Targeted droplet digital PCR validated the variant and quantified the mosaicism in other tissues. The variant was detected at 33% in temporal lobe tissue but was absent from blood and healthy skin. We provide molecular confirmation of the clinical diagnosis of NSS. Our data extends the histopathological spectrum of KRAS G12C mosaicism beyond nevus sebaceous to involve brain tissue and, more specifically, hippocampal sclerosis.

Evaluation of Crizotinib Treatment in a Patient With Unresectable GOPC-ROS1 Fusion Agminated Spitz Nevi.

IMPORTANCE: Spitz nevi are benign melanocytic neoplasms that classically present in childhood. Isolated Spitz nevi have been associated with oncogenic gene fusions in approximately 50% of cases. The rare agminated variant of Spitz nevi, thought to arise from cutaneous genetic mosaicism, is characterized by development of clusters of multiple lesions in a segmental distribution, which can complicate surgical removal. Somatic single-nucleotide variants in the HRAS oncogene have been described in agminated Spitz nevi, most of which were associated with an underlying nevus spilus. The use of targeted medical therapy for agminated Spitz nevi is not well understood. OBSERVATIONS: A girl aged 30 months presented with facial agminated Spitz nevi that recurred rapidly and extensively after surgery. Owing to the morbidity of further surgery, referral was made to a molecular tumor board. The patient's archival nevus tissue was submitted for extended immunohistochemical analysis and genetic sequencing. Strong ROS1 protein expression was identified by immunohistochemistry. Consistent with this, analysis of whole-genome sequencing data revealed GOPC-ROS1 fusions. These results indicated likely benefit from the oral tyrosine kinase inhibitor crizotinib, which was administered at a dosage of 280 mg/m2 twice daily. An excellent response was observed in all lesions within 5 weeks, with complete flattening after 20 weeks. CONCLUSIONS AND RELEVANCE: Given the response following crizotinib treatment observed in this case, the kinase fusion was believed to be functionally consequential in the patient's agminated Spitz nevi and likely the driver mutational event for growth of her nevi. The repurposing of crizotinib for GOPC-ROS1 Spitz nevi defines a new treatment option for these lesions, particularly in cases for which surgery is relatively contraindicated.

A Systematic Review of Intra-abdominal Tissue Expansion for the Treatment of Exomphalos Major and a Case Report Describing a Refinement of the Technique.

ABSTRACT: The management of complex exomphalos major is difficult, and traditional techniques fail to address the visceroabdominal disproportion in the most severe cases. Intra-abdominal tissue expansion is a novel technique and has been used in a small number of patients to safely increase the intra-abdominal volume and allow the reduction of viscera and subsequent closure of the abdominal domain. We review 7 published reports of this technique and add a case report describing our refinement of the technique. We propose that the use of multiple expanders placed in the intra-abdominal preperitoneal space, when expanded slowly, can allow safe reduction of viscera and immediate direct closure of the musculofascial layer of the abdomen.

The psychosocial impact of congenital hand and upper limb differences on children: a qualitative study.

This qualitative study explored the psychosocial concerns of children born with congenital hand and upper limb differences (CHULDs) from the point of view of these children and their parents. Qualitative, in-depth, semi-structured interviews were conducted face-to-face with eight parent-child dyads. Open format questions allowed spontaneous emergence of relevant themes, followed by guided questioning. Thematic analysis of audio-recorded and transcribed interviews found that children as young as 5 years old had unique and meaningful opinions about their CHULD, of which parents were sometimes unaware. Children reported that unsolicited questions from peers caused significant stress, and this increased around the time of surgery. All children used planned responses to peers as an effective coping mechanism. Children also identified positive aspects of their difference, including an increased sense of determination and an appreciation for being unique. Strategies that may improve psychosocial outcomes for children with CHULDs are discussed.Level of evidence: IV.

Surgical Management of Intramuscular Venous Malformations.

BACKGROUND: Intramuscular venous malformations, often erroneously called "intramuscular hemangiomas," present to pediatric orthopaedic surgeons either as a differential diagnosis of tumor or as a cause of muscle pain. Treatment options include injection sclerotherapy or surgery. There is some literature to indicate that sclerotherapy can reduce pain, but little evidence on the effectiveness of surgery. The primary aim of this study was to evaluate the efficacy of surgical resection for intramuscular venous malformations, with a secondary aim to evaluate the natural history and presentation of intramuscular venous malformations to improve clinician understanding of this condition. METHODS: A retrospective chart analysis was performed of cases identified from a vascular anomalies database from January 2004 and December 2018. Primary outcome was change in preoperative and postoperative pain. Natural history of the lesion was assessed, including age when the lesion was first noticed, when it became painful, and when it required treatment. RESULTS: Fifty-four cases were identified in the study period of which 40 underwent surgery. Pain improved in 36 of 39 patients (92.3%) who had pain before surgery and 29 (74.4%) were pain free after surgery. All 13 patients who required whole muscle excision to resect the lesion experienced an improvement in pain and 10 (76.9%) were pain free. A history of previous intervention, with surgery or sclerotherapy showed a trend towards less successful surgical outcomes. Patients presented across a wide age range from infancy to adulthood, but the most common presentation was pain with exercise between 9 and 16 years of age, with presence of a mass in about half of cases. CONCLUSIONS: Surgery, when performed by a surgeon with appropriate experience, is an effective first-line treatment for painful intramuscular venous malformations, offering pain relief in the majority of cases. Magnetic resonance imaging and ultrasound are diagnostic in most cases. The majority of lesions are resectable, meaning they can be removed with a margin leaving a functional limb. Sometimes resection of a whole muscle is required. LEVEL OF EVIDENCE: Level IV-case series.

Pitfalls and Promise of 3-dimensional Image Comparison for Craniofacial Surgical Assessment.

Three-dimensional (3D) photography is becoming widely used in plastic surgery. It provides an accurate and reproducible record of the facial surface anatomy and could be a versatile tool for treatment planning and assessment. However, the existing software tools available for the assessment of 3D facial imaging often give highly misleading results. The goal of this special topic article is to give clinicians an insight into methods of 3D image assessment and explain the reasons why results may be misleading. We point toward the advantages of an alternative approach using "nonrigid surface registration" for the comparison of pre- and postsurgical images. This approach is compared with the regular rigid surface registration, and this is illustrated by the assessment of a child with Crouzon syndrome before and after LeFort III osteotomy and distraction. Findings of the standard method imply that changes have occurred that are anatomically not possible, whereas the alternative approach indicates realistic changes. Furthermore, we demonstrate an exciting capacity of 3D image analysis to construct reference populations of normal head size and shape. These can be used to assess the parts of the head that are normal and abnormal pre- and posttreatment of the same child. We conclude that, while 3D image analysis has great potential in surgical assessment, existing software does not always give an adequate assessment. Collaboration among surgeons and engineering and computer science specialists should be encouraged. This way, more comprehensive and accurate techniques in patient assessment and surgical planning can be developed and applied in clinical practice.

'Operating is the easy part': Surgeons' decision-making processes and responses to parental requests for elective paediatric appearance-altering facial surgery.

Some parents request elective appearance-altering facial surgery for their children for cosmetic, psychological and/or social reasons. These operations have attracted controversy in the bioethics literature. They are also the subject of professional guidance documents internationally, which leave much to individual practitioners' discretion. Despite their controversial nature, very little is known about surgeons' practices and decision-making processes regarding these operations. Individual semi-structured interviews were conducted by 22 plastic surgeons and oral and maxillofacial surgeons in Australia to explore their descriptions of the types of parental requests they receive for these operations, their decision-making processes and their responses to these requests. Interviews were audio-recorded, transcribed and analysed using inductive content analysis. Surgeons reported parents often request these operations to alleviate or prevent teasing and associated psychosocial distress. However, surgeons expressed concern some parents may be requesting surgery to further their own interests, rather than their child's. Surgeons reported considering multiple factors when making decisions about the ethical justifiability of facilitating these parental requests, including children's wishes about surgery, the severity of the facial difference, the child's growth stage and parents' reasons for requesting. Although most surgeons appeared comfortable denying parental requests when they believe surgery is not in the child's best interests, some indicated they will acquiesce if parents persist. This study provides insights into surgeons' practices and decision-making processes regarding elective paediatric appearance-altering facial surgery requested by parents. It also highlights implications for clinical practice and education, and identifies areas warranting further research.

Prolonged antibiotic treatment for infected low flow vascular malformations.

BACKGROUND: Infection in low flow malformations is difficult to diagnose and treat. Initial presentation can be followed by cycles of recurrent infection lasting several years. The optimal duration of antibiotic therapy to prevent recurrence of infection has not been established. METHODS: All cases of infection in low flow malformations at the Royal Children's Hospital over a ten-year period were reviewed. Clinical markers of infection and duration of initial antibiotic treatment were correlated with the development of recurrent episodes of infection. RESULTS: Twenty-one patients met criteria for inclusion. Nineteen were diagnosed as lymphatic malformations and two as venous malformations. The majority of patients (13 or 62%) received a prolonged course of six weeks or more of antibiotics. Eleven (52%) patients went on to have recurrent infections, but these were significantly less likely to be in those treated with a long course of antibiotics (Fisher's exact test, p=0.026). In only 12 of 21 cases could a bacterium be grown. Elevated CRP was the most consistent abnormal laboratory finding in infection. CONCLUSIONS: Longer courses of antibiotics reduce the risk of recurrent infection in low-flow vascular malformations. We recommend an antibiotic course of three months or more at the initial presentation of infection in a low flow malformation. Elevated CRP is the most sensitive test for diagnosis of infection in low-flow malformations. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: III.

Consensus statement for the treatment of infantile haemangiomas with propranolol.

Although most infantile haemangiomas do not require treatment due to a natural history of spontaneous involution, some require early intervention. The Australasian Vascular Anomalies Network and the Australasian Paediatric Dermatology Network have developed a consensus statement for the treatment of infantile haemangiomas with oral propranolol. Infants with haemangiomas that are life threatening, at risk of ulceration, or at risk of causing a significant functional impairment, psychological impact or physical deformity should be treated early with oral propranolol. Oral propranolol is safe and effective and in most healthy infants oral propranolol can be started in an outpatient setting.

Wound management of ulcerated haemangioma of infancy - an audit.

Haemangioma of infancy, a benign tumour of blood vessels, is the most common tumour of infancy. Ulceration, the most common complication, presents a unique wound care challenge. A retrospective audit of medical records of children with haemangioma of infancy who presented to the Royal Children's Hospital, Melbourne, Australia, between January 2000 and December 2014 was undertaken with an aim to examine wound management of ulcerated haemangioma of infancy. In total, 535 hospital medical records were identified as suitable, of which 352 were randomly selected and audited, of which 84 patients had ulcerated haemangioma of infancy, and 62 were subject to wound management. Of these, 35 were successfully managed by wound dressings, 9 were not fully healed at the time of last review, and 18 were referred for surgical excision. Patients attended an average of five outpatient visits, and the average time from presentation to documented healing was 105 days. There were a total of 225 episodes of wound dressing, for which there was a documented follow-up appointment at which healing could be assessed. Although a wide range of dressings were used, there was no clear pattern of benefit of one dressing over another. Wounds were less likely to be healed after the use of a silver-impregnated dressing. Pain was poorly documented. Clinical assessment of whether wounds were infected was of no help in planning treatment. There is considerable variability in the management of this difficult wound group, and further prospective studies are required.

Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.

Paediatric fingertip composite grafts: Do they all go black?

BACKGROUND: Fingertip injuries are amongst the most frequently seen hand injuries in the paediatric population. The present study evaluated the composite graft survival rate in distal digital amputations with respect to injury type, amputation level and time to surgery. METHODS: We performed a retrospective review of patients who underwent composite grafting of fingertip injuries over an 11-year period at a paediatric hospital. All children who underwent non-vascularized replantation of amputated fingertips were included. Patients were excluded if they failed to attend at least one follow-up appointment. Demographic information was recorded. The nature and level of injury and time to surgery was also recorded. Graft viability was characterized as no take, partial take, or complete take. The number of secondary procedures and number and duration of follow-up appointments were recorded. RESULTS: A total of 105 patients underwent fingertip composite grafting, of whom 96 were suitable for inclusion in this study. The median age was 2.4 years (0-16 years); there were 48 boys (46%) and 57 girls (54%). Thirty-one patients had no graft take (32%), 50 patients had partial take (52%) and 15 patients had complete take (16%). Only two patients underwent secondary revision (2%). The median number of follow-up appointments was 4, and the mean follow-up time was 68 days. Time to surgery or level of amputation did not have a statistically significant influence on outcome. CONCLUSIONS: Over two-thirds of composite grafts in children showed some degree of take, albeit partially in the majority. Morbidity was low, and most children did not require further surgery.

GAPTrap: A Simple Expression System for Pluripotent Stem Cells and Their Derivatives.

The ability to reliably express fluorescent reporters or other genes of interest is important for using human pluripotent stem cells (hPSCs) as a platform for investigating cell fates and gene function. We describe a simple expression system, designated GAPTrap (GT), in which reporter genes, including GFP, mCherry, mTagBFP2, luc2, Gluc, and lacZ are inserted into the GAPDH locus in hPSCs. Independent clones harboring variations of the GT vectors expressed remarkably consistent levels of the reporter gene. Differentiation experiments showed that reporter expression was reliably maintained in hematopoietic cells, cardiac mesoderm, definitive endoderm, and ventral midbrain dopaminergic neurons. Similarly, analysis of teratomas derived from GT-lacZ hPSCs showed that ß-galactosidase expression was maintained in a spectrum of cell types representing derivatives of the three germ layers. Thus, the GAPTrap vectors represent a robust and straightforward tagging system that enables indelible labeling of PSCs and their differentiated derivatives.

Isolation of human lymphatic endothelial cells by multi-parameter fluorescence-activated cell sorting.

Lymphatic system disorders such as primary lymphedema, lymphatic malformations and lymphatic tumors are rare conditions that cause significant morbidity but little is known about their biology. Isolating highly pure human lymphatic endothelial cells (LECs) from diseased and healthy tissue would facilitate studies of the lymphatic endothelium at genetic, molecular and cellular levels. It is anticipated that these investigations may reveal targets for new therapies that may change the clinical management of these conditions. A protocol describing the isolation of human foreskin LECs and lymphatic malformation lymphatic endothelial cells (LM LECs) is presented. To obtain a single cell suspension tissue was minced and enzymatically treated using dispase II and collagenase II. The resulting single cell suspension was then labelled with antibodies to cluster of differentiation (CD) markers CD34, CD31, Vascular Endothelial Growth Factor-3 (VEGFR-3) and PODOPLANIN. Stained viable cells were sorted on a fluorescently activated cell sorter (FACS) to separate the CD34(Low)CD31(Pos)VEGFR-3(Pos)PODOPLANIN(Pos) LM LEC population from other endothelial and non-endothelial cells. The sorted LM LECs were cultured and expanded on fibronectin-coated flasks for further experimental use.

Three patterns of fronto-orbital remodeling for metopic synostosis: comparison of cranial growth outcomes.

BACKGROUND: The authors compared cranial growth across three patterns of fronto-orbital remodeling for metopic synostosis. METHODS: The authors reviewed all patients who underwent fronto-orbital remodeling for isolated metopic synostosis between 2006 and 2009. Inclusion criteria consisted of patients with preoperative, short-term postoperative (4 to 12 months), and long-term postoperative (>36 months) three-dimensional photographs. Patients were categorized by fronto-orbital remodeling pattern: group 1, retrocoronal; group 2, partial coronal; and group 3, precoronal. Head circumference, minimum frontal breadth (ft-ft), and maximum cranial length were measured by three-dimensional photographs, converted to standard Z scores, and compared. RESULTS: Thirty-one patients met inclusion criteria (group 1, n=12; group 2, n=10; and group 3, n=9). Group 1 presented with the greatest phenotypic severity. From preoperative to short-term postoperative assessment, head circumference Z scores rose for group 1 but dropped for groups 2 and 3, and the three groups demonstrated equivalent increases in minimum frontal breadth Z scores. From short-term to long-term postoperatively, the three groups demonstrated similar stability in head circumference Z scores but decreased minimum frontal breadth Z scores. From preoperatively to long-term postoperatively, head circumference Z scores rose for group 1 but fell for groups 2 and 3 (change in Z score, 0.5, -0.5, and -0.7, respectively; p=0.06) and the three groups demonstrated equivalent drops in minimum frontal breadth Z scores. Across preoperative to short-term postoperative and preoperative to long-term postoperative assessment, group 1 displayed the least drop in maximum cranial length Z scores. CONCLUSIONS: Retrocoronal patterns of fronto-orbital remodeling provide long-term gains in head circumference percentile and the least growth impairment in cranial length. Irrespective of osteotomy design, expansion in frontal breadth relapses significantly over time. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Infantile haemangiomas that failed treatment with propranolol: clinical and histopathological features.

AIM: To describe the clinical and histopathological characteristics of infantile haemangiomas that failed treatment with oral propranolol . DESIGN: This study is a case series from the vascular birthmarks clinic at Royal Children's Hospital, Melbourne. PATIENTS: The patients for this study were infants who commenced treatment with oral propranolol before 6 months of age and who were treated for at least 4 months without a satisfactory result. For histology and immunohistochemistry, tissue from the four non-responding patients who subsequently underwent surgical excision was matched with four historical controls. OUTCOME MEASURES: Based on medical record review and photographic assessments, infants were defined as having failed treatment with oral propranolol if the infantile haemangioma either continued to grow or showed 20% improvement or less. Tissue sections were examined for tissue structure, mast cells, sympathetic innervations and beta-2 adrenergic receptor expression, and the number of mast cells and beta-2 adrenergic positive cells. RESULTS: From a group of 135 infants who met the inclusion criteria, 14 infants failed propranolol treatment. Eleven of these infants had focal facial haemangiomas. No difference was seen in tissue morphology, tissue innervations, beta-2 adrenergic receptor expression, cell number or mast cell distribution, and number between non-responding and control haemangiomas. CONCLUSION: We report a treatment failure rate of 10%, which is higher than previously reported. Focal facial lesions failed to respond twice as frequently as other types of haemangioma. No histopathological reason was identified to indicate why some haemangiomas failed to respond.