Transgenic mice with an R342X mutation in Phf6 display clinical features of Börjeson-Forssman-Lehmann Syndrome.

The PHF6 mutation c.1024C > T; p.R342X, is a recurrent cause of Börjeson-Forssman-Lehmann Syndrome (BFLS), a neurodevelopmental disorder characterized by moderate-severe intellectual disability, truncal obesity, gynecomastia, hypogonadism, long tapering fingers and large ears (MIM#301900). Here, we generated transgenic mice with the identical substitution (R342X mice) using CRISPR technology. We show that the p.R342X mutation causes a reduction in PHF6 protein levels, in both human and mice, from nonsense-mediated decay and nonsense-associated alternative splicing, respectively. Magnetic resonance imaging studies indicated that R342X mice had a reduced brain volume on a mixed genetic background but developed hydrocephaly and a high incidence of postnatal death on a C57BL/6 background. Cortical development proceeded normally, while hippocampus and hypothalamus relative brain volumes were altered. A hypoplastic anterior pituitary was also observed that likely contributes to the small size of the R342X mice. Behavior testing demonstrated deficits in associative learning, spatial memory and an anxiolytic phenotype. Taken together, the R342X mice represent a good preclinical model of BFLS that will allow further dissection of PHF6 function and disease pathogenesis.

Strangers look sicker (with implications in times of COVID-19).

We animals have evolved a variety of mechanisms to avoid conspecifics who might be infected. It is currently unclear whether and why this "behavioral immune system" targets unfamiliar individuals more than familiar ones. Here I answer this question in humans, using publicly available data of a recent study on 1969 participants from India and 1615 from the USA. The apparent health of a male stranger, as estimated from his face, and the comfort with contact with him were a direct function of his similarity to the men in the local community. This held true regardless of whether the face carried overt signs of infection. I conclude that our behavioral immune system is finely tuned to degrees of outgroupness - and that cues of outgroupness are partly processed as cues of infectiousness. These findings, which were consistent across the two cultures, support the notion that the pathogens of strangers are perceived as more dangerous.

Treatment of Human Immunodeficiency Virus-Associated Facial Lipoatrophy With Hyaluronic Acid Filler Mixed With Micronized Cross-Linked Acellular Dermal Matrix.

BACKGROUND: Human immunodeficiency virus (HIV)-associated facial lipoatrophy (FLA) is a stigmatizing side effect associated with the use of highly active antiretroviral therapy. We sought to evaluate the safety and efficacy of the hyaluronic acid filler mixed with micronized cross-linked acellular dermal matrix (HA/MADM) in HIV-associated FLA. METHODS: We conducted an open-label safety and efficacy study in patients with HIV-associated FLA. Fourteen patients received single injection of the HA/MADM, and 13 patients completed the 24-week follow-up evaluation. Treatment efficacy, safety, and patient and physician satisfaction were evaluated. Repeated measure analysis of variance with post-hoc analysis with the Wilcoxon signed rank test was performed to compare and incorporate parameters at each time point. RESULTS: All 13 patients maintained a significant improvement of the Carruthers Lipoatrophy Severity Scale grade throughout the study period, along with improvement of the depressed volume due to lipoatrophy measured using a three-dimensional camera system. More than 80% of patients and physicians were satisfied with the treatment, and no treatment-related adverse events were reported, except for one case of transient subcutaneous nodule formation. CONCLUSION: Our study findings suggest that injectable HA/MADM is a potentially effective and safe treatment option for treating HIV-positive patients with FLA.

Facial recognition accuracy in photographs of Thai neonates with Down syndrome among physicians and the Face2Gene application.

Down syndrome (DS) is typically recognizable in those who present with multiple dysmorphism, especially in regard to facial phenotypes. However, as the presentation of DS in neonates is less obvious, a phenotype-based presumptive diagnosis is more challenging. Recently, an artificial intelligence (AI) application, Face2Gene, was developed to help physicians recognize specific genetic syndromes by using two-dimensional facial photos. As of yet, there has not been any study comparing accuracy among physicians or applications. Our objective was to compare the facial recognition accuracy of DS in Thai neonates, using facial photographs, among physicians and the Face2Gene. Sixty-four Thai neonates at Thammasat University Hospital, with genetic testing and signed parental consent, were divided into a DS group (25) and non-DS group (39). Non-DS was further divided into unaffected (19) and those affected with other syndromes (20). Our results revealed physician accuracy (89%) was higher than the Face2Gene (81%); however, the application was higher in sensitivity (100%) than physicians (86%). While this application can serve as a helpful assistant in facilitating any genetic syndrome such as DS, to aid clinicians in recognizing DS facial features in neonates, it is not a replacement for well-trained doctors.

Genotype and phenotype in 18 Chinese patients with Coffin-Siris syndrome.

Coffin-Siris syndrome (CSS, MIM# 1359200) is a multisystem congenital disorder characterized by coarse facial features, hypoplasia of the fifth digits and nails, and intellectual disability. It is a genetically heterogeneous condition caused by pathogenic variants in genes encoding proteins of the BAF (BRG1-associated factors) chromatin modeling complex and its downstream transcriptional factor. To date over 220 CSS individuals with pathogenic variants found have been described in the literature. This case series reported 18 molecularly confirmed Chinese individuals (17 with ARIDIB (OMIM*614556) variants and one with SMARCB1 (OMIM*601607) variant) from 17 unrelated families in Hong Kong. The clinical features of these 18 Chinese CSS patients together with two previously reported Chinese patients with ARID1B variants were reviewed. Among the 19 Chinese patients with ARID1B variants, our data suggested a lower prevalence of feeding problem, autistic features, agenesis of corpus callosum (ACC) or partial/hypoplasia of corpus callosum, and sparse hair when compared with previous reports. There was appearing higher prevalence of digital hypoplasia. Digital hypoplasia was observed to become less noticeable with time in some patients. This report highlighted the age-dependent phenotypic presentation of CSS and ethnicity-related effect on ARID1B-CSS phenotype. Moreover, this series included the first family with molecularly confirmed maternal somatic mosaicism of ARID1B variant leading to familial CSS recurrence.

Twenty-year follow-up of the facial phenotype of Brazilian patients with Sotos syndrome.

Sotos syndrome is characterized by overgrowth starting before birth through childhood with intellectual disability and craniofacial anomalies. The majority of patients are large for gestational age with developmental delay or intellectual disability. The majority of cases are caused by pathogenic variants in NSD1. The most consistent physical features in this disorder are facial dysmorphisms including prominent forehead, downslanted palpebral fissures, prognathism with a pointed chin, and a long and narrow face. We present a follow-up to a cohort of 11 individuals found to harbor heterozygous, pathogenic, or likely pathogenic variants in NSD1. We analyzed the facial dysmorphisms and the condition using retrospective over 20 years. Among these patients, followed in our medical genetics outpatient clinic for variable periods of time, all had a phenotype compatible with the characteristic Sotos syndrome facial features, which evolved with time and became superimposed with natural aging modifications. We present here a long-term follow-up of facial features of Brazilian patients with molecularly confirmed Sotos syndrome. In this largest Brazilian cohort of molecularly confirmed patients with Sotos syndrome to date, we provide a careful description of the facial phenotype, which becomes less pronounced with aging and possibly more difficult to recognize in adults. These results may have broad clinical implications for diagnosis and add to the global clinical delineation of this condition.

The point-of-care use of a facial phenotyping tool in the genetics clinic: Enhancing diagnosis and education with machine learning.

Computer-assisted pattern recognition platforms, such as Face2Gene® (F2G), can facilitate the diagnosis of children with rare genetic syndromes by comparing a patient's features to known genetic diagnoses. Our work designed, implemented, and evaluated an innovative model of care in clinical genetics in a heterogeneous and multicultural patient population that utilized this facial phenotyping software at the point-of-care. We assessed the performance of F2G by comparing the suggested diagnoses to the patient's confirmed molecular diagnosis. Providers' overall experiences with the technology and trainees' educational experiences were assessed with questionnaires. We achieved an overall diagnostic yield of 57%. This increased to 82% when cases diagnosed with syndromes not recognized by F2G were removed. The mean rank of a confirmed diagnosis in the top 10 was 2.3 (CI 1.5-3.2) and the mean gestalt score 37.6%. The most commonly suggested diagnoses were Noonan syndrome, mucopolysaccharidosis, and 22q11.2 deletion syndrome. Our qualitative assessment revealed that clinicians and trainees saw value using the tool in practice. Overall, this work helped to implement an innovative patient care delivery model in clinical genetics that utilizes a facial phenotyping tool at the point-of-care. Our data suggest that F2G has utility in the genetics clinic as a clinical decision support tool in diverse populations, with a majority of patients having their eventual diagnosis listed in the top 10 suggested syndromes based on a photograph alone. It shows promise for further integration into clinical care and medical education, and we advocate for its continued use, adoption and refinement along with transparent and accountable industrial partnerships.

Quantitative assessment of Bell's palsy-related facial thermal asymmetry using infrared thermography: A preliminary study.

The temperature distribution of normal human skin is symmetrical. Facial paralysis generally changes this thermal symmetry. The aim of this study is to analyze facial thermal asymmetry during the early onset of Bell's palsy, and to assess the feasibility of the diagnosis of early-onset Bell's palsy using infrared thermography (IRT). Fifteen subjects with Bell's palsy and 15 healthy volunteers were considered in this study. The infrared thermal images of the front, left, and right sides of all the subjects were collected and analyzed. Each group of facial thermograms was divided into 16 symmetrical regions of interest (ROIs) with respect to the left and right sides. Three different temperature difference calculation methods were used to express the degree of thermal symmetry between the left- and right-side ROIs, namely, the mean temperature difference (ΔTroi), maximum temperature difference (ΔTmax), and minimum temperature difference (ΔTmin). Among the facial ROIs, there were significant differences in the thermal symmetries of the frontal region, medial canthus region, and infraorbital region between subjects with and without Bell's palsy (p < 0.05). Based on the results, ΔTroi was more effective than the other two methods for the diagnosis of early-onset Bell's palsy. The area under the ROC curve (AUC) of ΔTroi in the infraorbital region was 0.818; and the sensitivity and specificity were 0.867 and 0.800, respectively. Subjects with early-onset Bell's palsy exhibited thermal asymmetry on the left and right sides of their faces. The diagnosis of early-onset Bell's palsy using IRT is therefore necessary. Nevertheless, more effective thermal symmetry analysis methods will be investigated further in future research.

Interhemispheric transfer of post-amputation cortical plasticity within the human somatosensory cortex.

Animal models reveal that deafferenting forelimb injuries precipitate reorganization in both contralateral and ipsilateral somatosensory cortices. The functional significance and duration of these effects are unknown, and it is unclear whether they also occur in injured humans. We delivered cutaneous stimulation during functional magnetic resonance imaging (fMRI) to map the sensory cortical representation of the intact hand and lower face in a group of chronic, unilateral, upper extremity amputees (N = 19) and healthy matched controls (N = 29). Amputees exhibited greater activity than controls within the deafferented former sensory hand territory (S1f) during stimulation of the intact hand, but not of the lower face. Despite this cortical reorganization, amputees did not differ from controls in tactile acuity on their intact hands. S1f responses during hand stimulation were unrelated to tactile acuity, pain, prosthesis usage, or time since amputation. These effects appeared specific to the deafferented somatosensory modality, as fMRI visual mapping paradigm failed to detect any differences between groups. We conclude that S1f becomes responsive to cutaneous stimulation of the intact hand of amputees, and that this modality-specific reorganizational change persists for many years, if not indefinitely. The functional relevance of these changes, if any, remains unknown.

Growth charts in Kabuki syndrome 1.

Kabuki syndrome (KS, KS1: OMIM 147920 and KS2: OMIM 300867) is caused by pathogenic variations in KMT2D or KDM6A. KS is characterized by multiple congenital anomalies and neurodevelopmental disorders. Growth restriction is frequently reported. Here we aimed to create specific growth charts for individuals with KS1, identify parameters used for size prognosis and investigate the impact of growth hormone therapy on adult height. Growth parameters and parental size were obtained for 95 KS1 individuals (41 females). Growth charts for height, weight, body mass index (BMI) and occipitofrontal circumference were generated in standard deviation values for the first time in KS1. Statural growth of KS1 individuals was compared to parental target size. According to the charts, height, weight, BMI, and occipitofrontal circumference were lower for KS1 individuals than the normative French population. For males and females, the mean growth of KS1 individuals was -2 and -1.8 SD of their parental target size, respectively. Growth hormone therapy did not increase size beyond the predicted size. This study, from the largest cohort available, proposes growth charts for widespread use in the management of KS1, especially for size prognosis and screening of other diseases responsible for growth impairment beyond a calculated specific target size.

3D facial morphometry in Italian patients affected by Aicardi syndrome.

Aicardi syndrome (AIC) is a rare congenital neurodevelopmental disorder of unknown etiology, that affects almost exclusively females, originally characterized by corpus callosum agenesis, chorioretinal lacunae, and infantile spasms. The current diagnostic criteria also include qualitative facial features (prominent premaxilla, upturned nasal tip, decreased nasal bridge angle, sparse lateral eyebrows, and microphthalmia) that still need quantification. A three-dimensional (3D) photogrammetric assessment of 11 Italian females, age 7-32 years, who satisfied AIC criteria, was performed. Linear distances and angles were computed from soft-tissue facial landmarks coordinates. The z-score values were calculated using data of 850 healthy reference females matched for age and compared by Mann-Whitney test (p < .01). Patients showed a shorter philtrum and right side orbital height (mean z-scores: -1.7, -0.9), shorter superior, middle, and inferior facial depths (mean z-scores: -1.3, -2.2, -2.3), and a smaller length of mandibular ramus (mean z-score: -2.1); conversely, they showed larger nasal and lower facial widths, and lower facial convexity (mean z-scores: 1.7, 1.4, 2.4). The inclinations of the orbit versus the true horizontal were increased bilaterally (mean z-scores: 1.8, 1.1). Some common facial abnormalities were quantified in AIC patients using a noninvasive instrument. They may help clinicians in performing a definite AIC diagnosis in atypical or doubt cases.

Anatomy Behind the Facial Overfilled Syndrome: The Transverse Facial Septum.

BACKGROUND: The midface is an area of high demand for minimally invasive cosmetic procedures, that is, soft-tissue filler injections. OBJECTIVE: To investigate the functional anatomy behind the facial overfilled syndrome observed after soft-tissue filler injections. MATERIALS AND METHODS: The clinical part of the study enrolled 25 volunteers (12 men and 13 women, Caucasians); the anatomical part included 72 fresh frozen cephalic specimens obtained from 32 male and 40 female body donors. 3D surface scanning procedures were applied to calculate the maximal anterior projection of the midface. RESULTS: Upon smiling, the point of maximal anterior projection shifted cranially in men by 12.43 ± 8.8 mm (difference between resting and smiling; p < .001) and by 8.75 ± 4.1 mm in women (p < .001). Cadaveric dissections identified a septum originated from the underside of the zygomaticus major muscle forming a transversely running boundary between the buccal space and the deep midfacial fat compartments. CONCLUSION: Facial overfilled syndrome can potentially be explained by the presence of the transverse facial septum. Dynamic filling-injecting small amounts of filler and asking the patient to smile repeatedly during the procedure-seems to be a viable way to avoid this adverse event during soft-tissue filler injection.

Detection of subclinical Harlequin syndrome in pediatric patients.

BACKGROUND: Harlequin syndrome presents as differences in facial coloring due to unilateral flushing. This is the result of the inability to flush on the affected side due to the disruption of vasomotor and sudomotor sympathetic activity. The neurologically intact side appears flushed. A 2°C temperature difference between the flushed and nonflushed sides of the face has been detected in patients presenting with Harlequin syndrome. This difference in temperature might be detectable even in the absence of unilateral flushing, and this subclinical manifestation of the syndrome may occur more often than realized. AIM: To measure and compare the difference in the change in temperature on both sides of the face in patients with a thoracic epidural. METHODS: Fifteen pediatric patients receiving thoracic epidurals for the correction of pectus excavatum via Nuss procedure were enrolled. Temperature measurements on each side of the face were collected at three time points: prior to epidural placement in the holding area, one hour after epidural analgesia had been instituted, and after the patient awakened in the recovery area. The primary outcome is whether or not a temperature difference occurred between the two sides of the face over time. RESULTS: Comparing the pre-op temperature change to post-op temperature change for each side of the face, patient 2 had a large increase in temperature on the left side of the face with a decrease in temperature on the right side of the face. The largest observed difference between the changes in temperature from pre-op to post-op between the right and left sides of the face was 1.85°C in patient 2. This was more than two standard deviations from the mean difference in the patient population. Patient 15 also had a large difference in change in temperature from pre-op to post-op between the right and left sides of the face with an observed difference of 1.14°C, although this was not more than two standard deviations from the mean. None of the patients had unilateral facial flushing. CONCLUSION: Asymmetric effects or distribution of local anesthetic used in thoracic epidurals may result in asymmetric blockade of efferent sympathetic nervous system activity. This may cause differences in temperature between the two sides of the face without unilateral flushing. This phenomenon has previously been termed subclinical Harlequin syndrome. Subclinical Harlequin syndrome may be more common than anticipated and may be detected by comparing temperature differences in patients.

A Clinical Anti-Ageing Comparative Study of 0.3 and 0.5% Retinol Serums: A Clinically Controlled Trial.

BACKGROUND: Retinol influences the process of keratinization of the epidermis, which improves stratum corneum structure and reduces transepidermal water loss. It also significantly enhances mature skin by brightening hyperpigmentation and reducing the signs of photoageing. Cosmeceuticals are intended to both provide aesthetic effects for the skin and allow dermatological treatment. The aim of the study was to assess the rejuvenating effect of retinol serum on facial skin at concentrations of 0.3 and 0.5%, as well as any improvements in skin brightening and elasticity. MATERIALS AND METHODS: Thirty-seven volunteers were included in the study, after confirming tolerance. The novel formula was applied once daily to the face for a period of 12 weeks: one retinol concentration on the left side and the other on the right. The initial study with liquid crystal formula (study vehicle) was carried out for 8 weeks on 28 volunteers. Treatment efficiency was evaluated at baseline, and 56 and 84 days following treatment using the multi probe adapter and Fotomedicus imaging system. PRIMOS was used to measure skin surface roughness. The visual analogue scale method enabled the results to be determined by 3 independent specialists. RESULTS: Skin hyperpigmentation, unevenness, and wrinkles gradually decreased over the course of treatment, both on the left and right parts of the face. Adverse events were predominantly mild or moderate skin irritation. More frequent and more intense symptoms were observed on the left side (0.5%). CONCLUSION: Retinol in liquid crystal formulation is safe and provides significant clinical benefits associated with unification of skin colour, overall skin tone, skin elasticity, and moisture. Regular use of retinol typically results in brightening of the skin and reduced signs of ageing. The objective findings confirmed the effectiveness of the procedures.

Evaluation of Divine Proportions in Face and Smile of Patients With Unilateral Cleft Lip and Palate.

INTRODUCTION AND AIM: The facial view of patients with cleft lip and palate greatly affects their psychological well-being and usually leads to introspection. The aim of this study was to compare the face and smile of cleft lip and palate patients and normal population with divine proportion. METHOD: In this retrospective study, 20 female patients (14-25 years) with unilateral cleft lip and palate, who referred to Orthodontic Department of Mashhad School of Dentistry, were selected. The control group consisted of 10 normal female persons with ideal face and normal occlusion. After scanning photographs of full face, profile, and smile views of them, the divine proportions were measured by Photoshop software. Then the data were entered into SPSS software version 22 and analyzed using 2 sample independent t test. P value less than 0.05 were considered as significant. RESULTS: In the study group all proportions were significantly less than the golden proportion. Ls-Rcus/Rch-Rcus and Ls-Lcus/Lch-Lcus had the least difference and Sn-Sm/N-Sn and Sn-Sm/Sm-Me had the most. In the control group, all proportions except Ls-Lcus/Lch-Lcus and Ls-Rcus/Rch-Rcus, were less than the golden proportion. Sn-Sm/N-Sn had the most difference and N-Sn/Sm-Me had the least.Approximately all proportions in cleft patients were significantly different from normal population. Ls-Lcus/Lch-Lcus had the highest difference between study and control group; however, Tr-Sn/Tr-Me in both groups were equal. CONCLUSIONS: The differences between facial indices in cleft lip and palate patients, normal people and golden proportion were significant. As facial proportions of normal people in the authors' study were also different from divine proportions, the authors can conclude that to reach acceptable esthetic results, the authors can approximate patients to normal populations. Unfortunately, the patients with large bone defects, cannot reach to the "esthetic" divine proportion even after reconstructive surgery.

Validation of the Turkish version of the Sunnybrook facial grading system

Background/aim: To adapt the Sunnybrook facial grading system (SFGS) into Turkish and perform validation and reliability studies on the Turkish version. Materials and Methods: The original English version of the SFGS was translated into Turkish by performing a linguistic validity study based on international standards. The evaluators comprised 6 physicians. Evaluations were performed twice independently using the video recordings of 65 facial palsy patients. Synchronously, the House-Brackman facial grading system (HBFGS) was filled out to display concurrent validity. The intraclass correlation coefficient (ICC) and Cronbach's alpha was used for the examination of the inter- and intra-rater reliability. As another indication of reliability, the generalizability (G) was also examined. Results: The ICC for the inter-rater reliability for resting symmetry, symmetry of voluntary movement, synkinesis, and the composite score, which are 4 components of the SFGS, were determined, respectively, as 0.822, 0.956, 0.606, and 0.957 for the first evaluation, and 0.805, 0.965, 0.584, and 0.965 for the second evaluation. For the intra-rater reliability, the ICC were determined as 0.842, 0.956, 0.794, and 0.937, while the Cronbach's alpha coefficients were determined as 0.809, 0.956, 0.792, and 0.948, respectively. The G coefficient was determined as G = 0.772. For the concurrent validity, a strong correlation was found between the SFGS and HBFGS scores. Conclusion: The present study adapted the SFGS into Turkish, and demonstrated that the adapted scale was valid and reliable. The Turkish version can be used for the evaluation of facial palsy, the follow-up of treatment efficiency, and standardization in reporting outcomes with the international literature.

AbobotulinumtoxinA for Facial Rejuvenation: What Affects the Duration of Efficacy?

AbobotulinumtoxinA (Dysport) has a long history as a safe and effective treatment option for aesthetic rejuvenation. One of the key measures of botulinum toxin efficacy is the persistence of clinically meaningful results. The duration of efficacy depends on different factors, many of which can be controlled by the clinician to better achieve their desired results. In this review, we discuss how dose, individual patient variation, and injection technique affect the duration of botulinum toxins. Increased duration may result from increased dose or more precise placement of the toxin in the muscle. The varying anatomy and behavior of patients can affect duration as well. Measures of duration in clinical studies vary, but both a 1-grade improvement on the glabellar line severity scale and patient-reported outcomes are key measures. The clinical effects of Dysport can last up to 5 months, and patients in Dysport clinical studies remained satisfied with treatment for up to 6 months. Dysport has a legacy of safety, efficacy, and high subject satisfaction demonstrated through studies and clinical experience. Building on that legacy by correctly dosing the subject, properly accounting for the individual subject anatomy and behavior, and using specific injection techniques can help ensure that your patients have the longest lasting results.

Establishing a Standardized Facial Cosmetic Preinjection Safety Tool: The ACIST.

In the past 20 years, the American population has seen an increased demand for nonsurgical minimally invasive facial rejuvenation solutions for the aging process. This widespread and increased demand for cosmetic injections brings a greater propensity for complications and adverse events. Choosing suitable patients for dermal filler is essential, as is concrete knowledge of the factors related to adverse events; however, there was no standardized tool to facilitate this process. The Joint Commission's Universal Safety checklist tools have been integrated into hospital surgical operating rooms and ambulatory outpatient settings across America and internationally and have successfully reduced errors in patient safety and outcomes. This article establishes the importance of integrating the Assessment Cosmetic Injection Safety Tool (ACIST), a standardized preinjection safety tool, into the cosmetic practice to decrease the incidence of adverse events associated with dermal filler and to achieve optimal patient satisfaction and outcomes. The ACIST was designed from the scientific literature, piloted at an urban cosmetic practice in the southern United States, finalized on the basis of feedback from participating staff members at the pilot study center, and disseminated to cosmetic nurse injectors.

Rdh10 loss-of-function and perturbed retinoid signaling underlies the etiology of choanal atresia.

Craniofacial development is a complex process that involves sequential growth and fusion of the facial prominences. When these processes fail, congenital craniofacial anomalies can occur. For example, choanal atresia (CA) is a congenital craniofacial anomaly in which the connection between the nasal airway and nasopharynx is completely blocked. CA occurs in approximately 1/5000 live births and is a frequent component of congenital disorders such as CHARGE, Treacher Collins, Crouzon and Pfeiffer syndromes. However, the detailed cellular and molecular mechanisms underpinning the etiology and pathogenesis of CA remain elusive. In this study, we discovered that mice with mutations in retinol dehydrogenase 10 (Rdh10), which perturbs Vitamin A metabolism and retinoid signaling, exhibit fully penetrant CA. Interestingly, we demonstrate Rdh10 is specifically required in non-neural crest cells prior to E10.5 for proper choanae formation, and that in the absence of Rdh10, Fgf8 is ectopically expressed in the nasal fin. Furthermore, we found that defects in choanae development are associated with decreased cell proliferation and increased cell death in the epithelium of the developing nasal cavity, which retards invagination of the nasal cavity, and thus appears to contribute to the pathogenesis of CA. Taken together, our findings demonstrate that RDH10 is essential during the early stages of facial morphogenesis for the formation of a functional nasal airway, and furthermore establish Rdh10 mutant mice as an important model system to study CA.

Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 9 affected individuals.

PURPOSE: Describe the clinical and molecular findings of patients with Kabuki syndrome (KS) who present with hypoglycemia due to congenital hyperinsulinism (HI), and assess the incidence of KS in patients with HI. METHODS: We documented the clinical features and molecular diagnoses of 9 infants with persistent HI and KS via a combination of sequencing and copy-number profiling methodologies. Subsequently, we retrospectively evaluated 100 infants with HI lacking a genetic diagnosis, for causative variants in KS genes. RESULTS: Molecular diagnoses of KS were established by identification of pathogenic variants in KMT2D (n = 5) and KDM6A (n = 4). Among the 100 infants with HI of unknown genetic etiology, a KS diagnosis was uncovered in one patient. CONCLUSIONS: The incidence of HI among patients with KS may be higher than previously reported, and KS may account for as much as 1% of patients diagnosed with HI. As the recognition of dysmorphic features associated with KS is challenging in the neonatal period, we propose KS should be considered in the differential diagnosis of HI. Since HI in patients with KS is well managed medically, a timely recognition of hyperinsulinemic episodes will improve outcomes, and prevent aggravation of the preexisting mild to moderate intellectual disability in KS.