Poland-Möbius syndrome: a case report implicating a novel mutation of the PLXND1 gene and literature review.

BACKGROUND: Möbius (Moebius) and Poland's syndromes are two rare congenital syndromes characterized by non-progressive bilateral (and often asymmetric) dysfunction of the 6th and 7th cranial nerves and hypoplasia of the pectoral muscles associated with chest wall and upper limb anomalies respectively. Manifest simultaneously as Poland-Möbius (Poland-Moebius) syndrome, debate continues as to whether this is a distinct nosological entity or represents phenotypic variation as part of a spectrum of disorders of rhomboencephalic development. Etiological hypotheses implicate both genetic and environmental factors. The PLXND1 gene codes for a protein expressed in the fetal central nervous system and vascular endothelium and is thus involved in embryonic neurogenesis and vasculogenesis. It is located at chromosome region 3q21-q22, a locus of interest for Möbius syndrome. CASE PRESENTATION: We present the first report of a patient with Poland-Möbius syndrome and a mutation in the PLXND1 gene. A child with Poland-Möbius syndrome and a maternally inherited missense variant (NM_015103.2:ex14:c.2890G > Ap.V964M) in the PLXND1 gene is described. In order to contextualize these findings, the literature was examined to identify other confirmed cases of Poland-Möbius syndrome for which genetic data were available. Fourteen additional cases of Poland-Möbius syndrome with genetic studies are described in the literature. None implicated the PLXND1 gene which has previously been implicated in isolated Möbius syndrome. CONCLUSIONS: This report provides further evidence in support of a role for PLXND1 mutations in Möbius syndrome and reasserts the nosological link between Möbius and Poland's syndromes. LEVEL OF EVIDENCE: Level V, Descriptive Study.

Seminal Studies in Facial Reanimation Surgery: Consensus and Controversies in the Top 50 Most Cited Articles.

ABSTRACT: Facial paralysis can impair one's ability to form facial expressions that are congruent with internal emotion. This hinders communication and the cognitive processing of emotional experience. Facial reanimation surgery, which aims to restore full facial expressivity is a relatively recent undertaking which is still evolving. Due in large part to published techniques, refinements, and clinical outcomes in the scientific literature, consensus on best practice is gradually emerging, whereas controversies still exist.Taking stock of how the discipline reached its current state can help delineate areas of agreement and debate, and more clearly reveal a path forward. To do this, the authors have analyzed the 50 seminal publications pertaining to facial reanimation surgery. In longstanding cases, the free gracilis transfer emerges as a clear muscle of choice but the nerve selection remains controversial with prevailing philosophies advocating cross facial nerve grafts (with or without the support of an ipsilateral motor donor) or an ipsilateral motor donor only, of which the hypoglossal and nerve to masseter predominate. The alternative orthodoxy has refined the approach popularized by Gillies in 1934 and does not require the deployment of microsurgical principles. Although this citation analysis does not tell the whole story, surgeons with an interest in facial reanimation will find that this is a good place to start.

Impact of Glabellar Paralysis on Facial Expression of Emotion.

BACKGROUND: Many prospective patients remain wary of the effects that glabellar muscle paralysis may have on their ability to normally communicate emotion with their face. OBJECTIVE: We undertook a direct empirical test of the effects of glabellar onabotulinum toxin type A injections on the ability to convey 6 universally recognized facial expressions of emotion. METHODS: Fifty-two female subjects ("expressors") were recorded on hidden camera while viewing video clips intended as a mood induction procedure that stimulates the 6 cardinal emotions (amusement, anger, disgust, fear, sadness, surprise). The subjects were then injected with 25 units of onabotulinum toxin A in the glabellar region. The subjects returned 1 month later and were again recorded while being spontaneously induced to express emotion. All video clips from both time periods from the 10 maximal expressors were extracted and shown to a group of 31 "perceivers" who rated the facial expressions for intensity (Likert 1-7) and identity of emotion (percent correct emotion identified). RESULTS: Glabellar paralysis significantly diminished mean perceived intensity of anger (50.4% relative reduction, P < 0.001) and surprise (20.6% relative reduction, P < 0.001). The mean intensity of disgust increased (39.0%, P < 0.001). Importantly, however, glabellar paralysis did not result in a significant change in observers' ability to discern provoked cardinal emotions. CONCLUSIONS: We believe these findings provide a measure of reassurance to patients and their providers that the use of onabotulinum toxin A to paralyze the glabellar musculature for aesthetic purposes may not pose a meaningful risk to the overall ability to express emotion during social interaction.

Pediatric Cervicofacial Actinomycosis: Lessons From a Craniofacial Unit.

Actinomycosis is a rare disease that remains difficult to diagnose and manage. Prompted by 2 recent cases the authors sought evidence-based conclusions about best practice. A systematic review was conducted using standard PRISMA methodology. The study was registered prospectively (PROSPERO: CRD42018115064). Thirty-three children from 23 series are described. The mean age was 8 years (range 3-17). Fifty-five percent were female. Twenty cases involved bone (usually mandible); 13 cases involved cervicofacial soft tissue. Poor dental hygiene and oral trauma were implicated. The median diagnostic delay was 12 weeks (range 1-156 weeks). The median duration of definitive antibiotic therapy was 17 weeks (range 1-130 weeks). Although diagnostic delay did not correlate with number of surgeries, bony involvement was associated with more procedures (P = 0.008, unpaired t test). All (6) cases with residual infection had bony involvement (P = 0.06, Fisher exact test). Neither diagnostic delay nor number of surgeries significantly influenced infection-free outcome which, instead, relies on aggressive surgical debridement and prolonged antibiotic therapy. Mandibular involvement exhibits a higher surgical burden and chronicity in around a third of cases. As dental caries are implicated in mandibular disease, preventative strategies must focus on improving pediatric oral hygiene.

Universal Applicability of the Furlow Palatoplasty: Resident as Primary Surgeon in a Consecutive, Nonselective Series.

BACKGROUND: Questions persist regarding the general applicability of the Furlow palatoplasty technique, and thus, widespread adoption of its use has been uneven. This study describes a consecutive, nonselective series of primary Furlow palatoplasties. Highlighted is the unique fact that plastic surgical residents functioned as the primary surgeon for all steps of all procedures throughout the series. METHODS: A retrospective review was undertaken of all primary palatoplasties performed under the direction of the senior surgeon between December 2005 and April 2012. A stringent requirement for speech outcome reporting was patient age at the latest assessment of older than 4.5 years. Other measured parameters included fistula rate, incidence of secondary surgery, and procedure duration. RESULTS: Seventy-five patients were included in this study. Nasal resonance was rated as "normal" in 56.1% of the patients and "mildly hypernasal or better" in 95.1% of the patients. Articulation errors were detected in 14.6% of the patients, and symptoms related to nasal air emission were detected in 4.9% of the patients. Overall fistula rate was 5.3%. The following associations were detected: (1) Veau cleft type and procedure duration, P = 0.001; (2) resident year of training and procedure duration, P = 0.009; (3) developmental delay and resonance score, P = 0.002; (4) patient age at surgery and resonance score, P = 0.025; and (5) presence of syndrome and resonance score, P = 0.036. CONCLUSIONS: This nonselective series of consecutive Furlow palatoplasty procedures demonstrates that plastic surgical residents are able to match best published clinical results performing the entire procedure under the close supervision and guidance of an assisting surgical mentor.

Orthotic (helmet) therapy in the treatment of plagiocephaly.

OBJECT: The goal of this study was to review the current literature on orthotic (helmet) therapy use in the treatment of deformational plagiocephaly. METHODS: PubMed was used to search English articles using the medical subject headings "deformational plagiocephaly" and "orthosis," and "deformational plagiocephaly" and "helmet." RESULTS: Forty-two articles were found. There were no Class I studies, 7 Class II studies, 1 Class III study, and 13 Class IV studies. Cranial orthoses have been shown to be effective in treating deformational plagiocephaly. It continues to be debated as to whether the statistical significance of treatment with cranial orthoses compared with conservative therapies is clinically significant. Children older than 12 months of age with deformational plagiocephaly may still benefit from orthotic therapy. The long-term effects of orthotic therapy are controversial. CONCLUSIONS: There is a lack of Class I literature evidence supporting the use of helmet therapy in deformational plagiocephaly. There are controversies surrounding the use of orthotic therapy such as appropriate use, cost, use in older children, and long-term outcomes. Clinical indications for orthotic therapy need to be better defined with further research studies.

Unsupervised anomaly appraisal of cleft faces using a StyleGAN2-based model adaptation technique.

A novel machine learning framework that is able to consistently detect, localize, and measure the severity of human congenital cleft lip anomalies is introduced. The ultimate goal is to fill an important clinical void: to provide an objective and clinically feasible method of gauging baseline facial deformity and the change obtained through reconstructive surgical intervention. The proposed method first employs the StyleGAN2 generative adversarial network with model adaptation to produce a normalized transformation of 125 faces, and then uses a pixel-wise subtraction approach to assess the difference between all baseline images and their normalized counterparts (a proxy for severity of deformity). The pipeline of the proposed framework consists of the following steps: image preprocessing, face normalization, color transformation, heat-map generation, morphological erosion, and abnormality scoring. Heatmaps that finely discern anatomic anomalies visually corroborate the generated scores. The proposed framework is validated through computer simulations as well as by comparison of machine-generated versus human ratings of facial images. The anomaly scores yielded by the proposed computer model correlate closely with human ratings, with a calculated Pearson's r score of 0.89. The proposed pixel-wise measurement technique is shown to more closely mirror human ratings of cleft faces than two other existing, state-of-the-art image quality metrics (Learned Perceptual Image Patch Similarity and Structural Similarity Index). The proposed model may represent a new standard for objective, automated, and real-time clinical measurement of faces affected by congenital cleft deformity.

Parents of Children with Cleft Lip Exhibit Heightened Visual Attention to the Perioral Area.

Following high-quality surgical repair, children born with a cleft lip anomaly may still display lasting visual differences. We exposed control adults and parents of affected children to images of children with cleft deformity and compared their visual tracking patterns. The protocol investigated whether parental exposure to secondary cleft deformity heightens or diminishes visual attraction to this type of structural facial variation. Method: Twenty participants (10 control adults, 10 parents of affected children) assessed 40 colored images of children's faces while their eye movements were tracked. Twenty-four control images and 16 repaired cleft lip images were displayed to observers. Nine bilateral facial aesthetic zones were considered as regions of interest. Percentage of time visually fixating within each region, and statistical differences in fixation duration percentage between the two participant groups and across the bilateral regions of interest were analyzed. Results: While both groups of observers directed more visual attention to the nasal and oral regions of the cleft images than control images, parents of children with cleft lip spent significantly more time fixating on these areas (25% and 24% of the time, respectively) than did unaffected adults (14.6% and 19.3%; P < 0.001). Conclusions: These results demonstrate that parents of cleft lip children exhibit heightened attention to this type of facial difference relative to the naive observer. These findings highlight that observer profile can meaningfully influence the perception of a facial deformity. Awareness of this information may enhance communication between surgeon and parents of an affected child by providing added insight into parental perspective.

Impact of Surgical Rejuvenation on Visual Processing and Character Attribution of Faces.

Background: This study considers observers' reflexive responses to the rejuvenated face, and how instinctive responses relate to subjective judgment. We investigated observers' reflexive perception of faces both pre and post surgical intervention during the early stages of visual processing. Subjective character attribution for all test images was also assessed by the same observers. Method: Forty frontal facial images of 20 patients portraying the pre- and postoperative high superficial musculoaponeurotic system facelift along with variable concomitant procedures were studied. Nineteen lookzone regions were mapped post hoc onto each image. Forty observers examined the images, whereas an eye-tracking camera recorded their eye movements. Visual fixation data were recorded and analyzed. Observers also rated each image on the basis of five elemental positive character attributes. Results: A statistically coherent but nonsignificant (P > 0.05) trend was identified with the surgical intervention resulting in greater attention being paid to the central triangle region of the face with reduction in attention to the facial periphery. Facial rejuvenation significantly increased the subjective character ratings of all five positively valenced attributes tested. Average age estimate of the photos decreased significantly from 54 to 48.6 years (true average age of 57.4 years). Conclusions: We provide data illustrating both reflexive and subjective responses to facial rejuvenation. Observers reported a more favorable impression of the treated faces and evaluated them as being younger than their true age. A trend was detected for increased visual fixation of the central facial region following rejuvenation. Interpretation of these findings and indication for further research is provided.

A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes.

Clefts of the lip and/or palate (CL/P) are considered the most common form of congenital anomalies occurring either in isolation or in association with other clinical features. Van der woude syndrome (VWS) is associated with about 2% of all CL/P cases and is further characterized by having lower lip pits. Popliteal pterygium syndrome (PPS) is a more severe form of VWS, normally characterized by orofacial clefts, lower lip pits, skin webbing, skeletal anomalies and syndactyly of toes and fingers. Both syndromes are inherited in an autosomal dominant manner, usually caused by heterozygous mutations in the Interferon Regulatory Factor 6 (IRF6) gene. Here we report the case of a two-generation family where the index presented with popliteal pterygium syndrome while both the father and sister had clinical features of van der woude syndrome, but without any point mutations detected by re-sequencing of known gene panels or microarray testing. Using whole genome sequencing (WGS) followed by local de novo assembly, we discover and validate a copy-neutral, 429 kb complex intra-chromosomal rearrangement in the long arm of chromosome 1, disrupting the IRF6 gene. This variant is copy-neutral, novel against publicly available databases, and segregates in the family in an autosomal dominant pattern. This finding suggests that missing heritability in rare diseases may be due to complex genomic rearrangements that can be resolved by WGS and de novo assembly, helping deliver answers to patients where no genetic etiology was identified by other means.

Transient oblong anisocoria and orbital surgery.

We present a rare case of transient oblong (segmental) anisocoria occurring at the time of limited orbital surgery. Observation of this previously undescribed phenomenon prompted us to review the relevant anatomy and physiology of the iris and the pharmacokinetics of lidocaine as it pertains to surgery in the region of the eyelids and the orbit.

Bregmatic wormian bone and metopic synostosis.

We present a case of a 14-week-old girl with metopic synostosis and an incidental finding of a large, pentagonal bregmatic wormian bone. No prior photographic evidence of this combination of rare findings exists. An extensive review of the incidence, etiology, and significance of these unusual supernumerary cranial bones is provided in this study.

Toward a Universal Measure of Facial Difference Using Two Novel Machine Learning Models.

A sensitive, objective, and universally accepted method of measuring facial deformity does not currently exist. Two distinct machine learning methods are described here that produce numerical scores reflecting the level of deformity of a wide variety of facial conditions. METHODS: The first proposed technique utilizes an object detector based on a cascade function of Haar features. The model was trained using a dataset of 200,000 normal faces, as well as a collection of images devoid of faces. With the model trained to detect normal faces, the face detector confidence score was shown to function as a reliable gauge of facial abnormality. The second technique developed is based on a deep learning architecture of a convolutional autoencoder trained with the same rich dataset of normal faces. Because the convolutional autoencoder regenerates images disposed toward their training dataset (ie, normal faces), we utilized its reconstruction error as an indicator of facial abnormality. Scores generated by both methods were compared with human ratings obtained using a survey of 80 subjects evaluating 60 images depicting a range of facial deformities [rating from 1 (abnormal) to 7 (normal)]. RESULTS: The machine scores were highly correlated to the average human score, with overall Pearson's correlation coefficient exceeding 0.96 (P < 0.00001). Both methods were computationally efficient, reporting results within 3 seconds. CONCLUSIONS: These models show promise for adaptation into a clinically accessible handheld tool. It is anticipated that ongoing development of this technology will facilitate multicenter collaboration and comparison of outcomes between conditions, techniques, operators, and institutions.

Thin and superthin free flaps: An innovative approach to pediatric extremity reconstruction.

INTRODUCTION: Published standards for the management of open extremity fractures have improved limb salvage, fracture union, and deep infection rates, but the aesthetic and functional importance of our flap choices has been overlooked. Thin and superthin free flaps exhibit advantages over traditional free flaps in some situations but have seldom been reported in children. The aim of this paper is to present our experience of thin and superthin free flaps in pediatric extremity reconstruction. METHODS: Children (≤13 years) who underwent soft tissue reconstruction using a thin and superthin free flap following major extremity trauma are presented. RESULTS: Five patients (5 flaps) met the inclusion criteria. The median age was 9 (range 6-13). There were 3 Gustilo IIIB open fractures and 2 multiplanar degloving injuries. The median mangled extremity severity score (MESS) was 4 (range 2-6). The median time from injury to definitive soft tissue closure was 72 h (range 28-120 h). Four anterolateral thigh (ALT) flaps were raised as thin flaps, and 1 superficial circumflex iliac artery perforator (SCIP) was raised as a superthin flap. There was one re-exploration owing to venous congestion, and a second venous anastomosis was performed to enhance flap drainage. The same ALT flap exhibited necrosis at one margin, which was debrided and grafted before discharge. There were no other flap complications. No flap-related secondary surgeries were required. CONCLUSION: Thin and superthin free flaps are viable options in pediatric extremity reconstruction. They exhibit excellent aesthetic and functional contouring when a slender fasciocutaneous flap is needed, especially when body habitus renders traditional options unfavorable.

Impact of Surgical Rejuvenation on Visual Processing and Character Attribution of Periorbital Aging.

BACKGROUND: The perceptual response to aging changes in the periorbital region and the effects of surgical rejuvenation on that response have not been elucidated. The authors examined the reflexive visual response to periorbital aging before and after brow lift and upper blepharoplasty surgery and investigated how observers' character attributions of the images were affected by the rejuvenative intervention. METHODS: Preoperative and postoperative photographs were obtained of patients with brow ptosis and dermatochalasis who underwent brow lift and blepharoplasty. Forty observers examined each image while an infrared eye-tracking camera continuously recorded their eye movements. The observers rated the images with respect to character attributes (attractiveness, trustworthiness, sociability, healthiness, and capability) on a scale of one to seven. RESULTS: Fourteen patients who underwent brow lift and blepharoplasty were identified and studied. The surgical intervention was found to increase observers' attention to the eye and brow region, while decreasing relative attention to the forehead and lower eyelid areas; increase the two-dimensional surface area of the forehead and eye and brow zones in a manner directly associated with the measured changes in visual attention; and significantly increase the ratings for all five positively valanced character attributes compared with preoperative controls. CONCLUSIONS: The authors provide an important combination of explicit and implicit data illustrating how surgical rejuvenation unveils the periorbital region to the observer. This change in pattern of inspection was associated with an improvement in the perception of character.

Pediatric orbital fractures.

The clinical presentation and management of pediatric orbital fractures have many unique features that differentiate them from orbital injuries encountered in the adult population. An understanding of the particular anatomic and mechanical properties of pediatric orbital bone and soft tissue helps to explain most of these differences. This article reviews the epidemiology, anatomy, growth implications, pathomechanics, particular clinical features, assessment, and surgical management of pediatric orbital fractures.

Acute lymphocytic leukemia presenting as an isolated scalp nodule in an infant.

We describe the presentation and management of a patient referred for a presumed benign scalp lesion in infancy. The subcutaneous nodule was ultimately diagnosed as the first manifestation of acute lymphoblastic leukemia. We review leukemia cutis with special emphasis on the differential diagnosis of scalp nodules in infancy that may be encountered by the plastic surgeon.

Personalized quantification of facial normality: a machine learning approach.

What is a normal face? A fundamental task for the facial reconstructive surgeon is to answer that question as it pertains to any given individual. Accordingly, it would be important to be able to place the facial appearance of a patient with congenital or acquired deformity numerically along their own continuum of normality, and to measure any surgical changes against such a personalized benchmark. This has not previously been possible. We have solved this problem by designing a computerized model that produces realistic, normalized versions of any given facial image, and objectively measures the perceptual distance between the raw and normalized facial image pair. The model is able to faithfully predict human scoring of facial normality. We believe this work represents a paradigm shift in the assessment of the human face, holding great promise for development as an objective tool for surgical planning, patient education, and as a means for clinical outcome measurement.

PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development.

Recessive mutations in Post-GPI attachment to proteins 3 (PGAP3) cause the rare neurological disorder hyperphosphatasia with mental retardation syndrome 4 type (HPMRS4). Here, we report a novel homozygous nonsense mutation in PGAP3 (c.265C>T-p.Gln89*), in a 3-year-old boy with unique novel clinical features. These include decreased intrauterine fetal movements, dysgenesis of the corpus callosum, olfactory bulb agenesis, dysmorphic features, cleft palate, left ear constriction, global developmental delay, and hypotonia. The zebrafish functional modeling of PGAP3 loss resulted in HPMRS4-like features, including structural brain abnormalities, dysmorphic cranial and facial features, hypotonia, and seizure-like behavior. Remarkably, morphants displayed defective neural tube formation during the early stages of nervous system development, affecting brain morphogenesis. The significant aberrant midbrain and hindbrain formation demonstrated by separation of the left and right tectal ventricles, defects in the cerebellar corpus, and caudal hindbrain formation disrupted oligodendrocytes expression leading to shorter motor neurons axons. Assessment of zebrafish neuromuscular responses revealed epileptic-like movements at early development, followed by seizure-like behavior, loss of touch response, and hypotonia, mimicking the clinical phenotype human patients. Altogether, we report a novel pathogenic PGAP3 variant associated with unique phenotypic hallmarks, which may be related to the gene's novel role in brain morphogenesis and neuronal wiring.

Measuring visual attention to faces with cleft deformity.

BACKGROUND: Limited data are available regarding observers' visual attention to faces with congenital difference. We implemented eye tracking technology to examine this issue, as it pertains particularly to faces with cleft deformity. METHOD: Four hundred three observers assessed 273 clinical images, while their eye movements were unobtrusively tracked using an infrared sensor. Forty-one facial images of the repaired cleft lip, 137 images of other facial conditions, and 95 images of matched controls were assessed. Twenty facial regions of interest ("lookzones") were considered for all images observed. A separate cohort of 720 raters evaluated the images for attractiveness. Observer and image demographic information was collected. Visual fixation counts and durations were computed across all 20 lookzones for all images. The effect of a variety of variables on lookzone fixation was analyzed using factorial ANOVA testing. RESULTS: Cleft-repaired faces were rated as less attractive and drew observers' attention preferentially to the affected upper lip lookzone (p<.001). Images rated as less attractive garnered greater visual attention in the cleft-affected lookzones (p<.001). The eye tracking methodology demonstrated exquisite sensitivity to laterality of cleft deformity (p<.001). Individuals reporting a personal or a family history of facial deformity fixated more on the perioral region of cleft-repaired faces than did naïve observers (p<.001). CONCLUSION: These findings highlight the utility of eye tracking measures for understanding critical variables that influence the visual processing of faces with cleft deformity. The data may provide analytical tools for assessing surgical outcome and direct priority setting during surgeons' conversations with patients.