Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

[Clinical characteristics and whole exome sequencing results of patients with Möbius syndrome].

Objective: To analyze the clinical characteristics of patients with Möbius syndrome (MBS) and to explore likely pathogenic genes. Methods: Cross-sectional study. The study enrolled 18 sporadic MBS patients who visited the Eye Center of Beijing Tongren Hospital Affiliated to Capital Medical University from July 2018 to December 2021. All patients completed the general information questionnaire and underwent detailed ophthalmic examinations and general physical examinations. Seventeen patients received MRI examination of cranial nerves and the orbit. The peripheral venous blood of all patients and their nuclear family members was collected, the genomic DNA was extracted, and the pathogenic gene variations that may lead to MBS were identified by whole exome sequencing and bioinformatics analysis. Results: Among the 18 patients, there were 8 males and 10 females, and the age was (4.5±4.0) years (range, 8 months to 17 years). All patients showed congenital, bilateral or unilateral abduction deficit and facial weakness, which met the minimum diagnostic criteria of MBS. Among them, bilateral abduction deficit (16/18) and bilateral facial weakness (15/18) were more common. Nine patients were orthotopic in primary position, eight presented with esotropia, and one showed hypotropia. All patients had ametropia, of which 4 patients were diagnosed as amblyopia. Fifteen patients were also accompanied by other multiple congenital malformations, mainly characterized by abnormal development of glossopharynx (14/18) and limbs (5/18), and 7 patients were also accompanied by motor retardation. In addition, 9 patients had intrauterine exposure to adverse factors. Among the 17 patients who underwent MRI, 15 patients had bilateral hypoplasia of the abducens nerve, two had unilateral hypoplasia of the abducens nerve, 14 showed bilateral hypoplasia of the facial nerve, and three showed hypoplasia of the left facial nerve. Besides, some patients were also accompanied by hypoplasia of other cranial nerves, mainly the glossopharyngeal nerve and the hypoglossal nerve. No definite pathogenic variations were found by whole exome sequencing and bioinformatics analysis. Conclusions: The main clinical features of MBS were congenital abduction deficit and facial weakness, with complicated manifestations and variable severity. MRI showed absence or thinning of the abducens nerve and the facial nerve. The results of MRI can be used as a supplement to the diagnostic criteria of MBS. The mutation detection rate of MBS was low, and half of patients had exposure to adverse factors during pregnancy, suggesting that there was a multifactorial pathogenic mechanism in MBS.

Workhorse Free Functional Muscle Transfer Techniques for Smile Reanimation in Children with Congenital Facial Palsy: Case Report and Systematic Review of the Literature.

BACKGROUND: Pediatric facial palsy represents a rare multifactorial entity. Facial reanimation restores smiling, thus boosting self-confidence and social integration of the affected children. The purpose of this paper is to present a systematic review of microsurgical workhorse free functional muscle transfer procedures with emphasis on the long-term functional, aesthetic, and psychosocial outcomes. MATERIALS AND METHODS: We performed a literature search of the PubMed database from 1995 to 2019 using the following search strategy: "facial paralysis"[Title/Abstract] OR "facial palsy"[Title]. We used as limits: full text, English language, age younger than 18 years, and humans. Two independent reviewers performed the online screening process using Covidence. Forty articles met the inclusion criteria. The protocol was aligned with the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and was registered at the International Prospective Register of Systematic Reviews (PROSPERO, CRD42019150112) of the National Institute for Health Research. RESULTS: Free functional muscle transfer procedures include mainly segmental gracilis, latissimus dorsi, and pectoralis minor muscle transfer. Facial reanimation procedures with the use of the cross-face nerve graft (CFNG) or masseteric nerve result in almost symmetric smiles. The transplanted muscle grows harmoniously along with the craniofacial skeleton. Muscle function and aesthetic outcomes improve over time. All children presented improved self-esteem, oral commissure opening, facial animation, and speech. CONCLUSIONS: A two-stage CFNG plus an FFMT may restore a spontaneous emotive smile in pediatric facial palsy patients. Superior results of children FFMT compared to adults FFMT are probably attributed to greater brain plasticity.

Differentiating Moebius syndrome and other congenital facial weakness disorders with electrodiagnostic studies.

INTRODUCTION: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW. METHODS: Forty-three subjects enrolled prospectively into a dedicated clinical protocol and had EDx evaluations, including blink reflex and facial and peripheral nerve conduction studies, with optional needle electromyography. RESULTS: MBS and hereditary congenital facial paresis (HCFP) subjects had low-amplitude cranial nerve 7 responses without other neuropathic or myopathic findings. Carriers of specific pathogenic variants in TUBB3 had, in addition, a generalized sensorimotor axonal polyneuropathy with demyelinating features. Myopathic findings were detected in individuals with Carey-Fineman-Ziter syndrome, myotonic dystrophy, other undefined myopathies, or CFW with arthrogryposis, ophthalmoplegia, and other system involvement. DISCUSSION: EDx in CFW subjects can assist in characterizing the underlying pathogenesis, as well as guide diagnosis and genetic counseling.

Contralateral Depressor Labii Inferioris Chemodenervation for Congenital Unilateral Lower Lip Palsy.

INTRODUCTION: Congenital unilateral lower lip palsy - also known as asymmetric crying facies - is isolated asymmetry of the lower lip unilaterally. It is characterized by isolated lower lip asymmetry during smiling and speech. Although etiology is unknown, depressor labii inferioris (DLI) weakness is hold responsible. AIM: Purpose of this study was to evaluate the effectiveness of contralateral depressor labii inferioris botulinum toxin injection on patients' concern levels and patient satisfaction. Ten units of botulinum toxin A injection was carried out to the healthy contralateral side. METHODOLOGY: Eleven patients were treated. Patients' pretreatment and posttreatment concern regarding asymmetry during speech and smiling was evaluated with a questionnaire. Patients' perception of treatment satisfaction was also evaluated with a questionnaire. RESULTS: Mean score related to concern about asymmetric appearance during smiling decreased from 1.6 ±â€Š0.8 to 0.5 ±â€Š0.5. Mean score related to concern about asymmetric appearance during speech decreased from 1.6 ±â€Š0.5 to 0.4 ±â€Š0.5. Eleven out of 11 patients reported improvement with speech whereas 10 out of 11 patients reported improvement with smiling. No weakness about oral competence was reported. CONCLUSION: Most congenital unilateral lower lip palsy patients are concerned regarding their asymmetric appearance while smiling or speaking. Chemodenervation of the contralateral DLI muscle reduces concern levels and has high patient satisfaction. Chemodenervation of the contralateral healthy DLI muscle is a valid, practical treatment option.

Developmental unilateral facial palsy in a newborn: six cases and literature review.

Unilateral facial palsy in a newborn is rarely caused by a developmental defect. It occurs either isolated or in the context of a syndrome. This article describes a multidisciplinary approach towards unilateral, isolated congenital facial palsy along with a literature review. We report six patients, three boys and three girls, who presented with a unilateral facial palsy at birth. Clinical assessment was performed by an ear-nose-throat (ENT) surgeon, a pediatric neurologist, and an ophthalmologist. Magnetic resonance imaging (MRI) of the posterior fossa and computerized tomography (CT) of the temporal bone were requested to exclude structural anomalies of the facial nerve. Imaging revealed the underlying cause in five patients out of six (80%), showing an ipsilateral facial nerve aplasia or hypoplasia. These findings point towards an underlying developmental defect and underscore the importance of MRI in the diagnostic work-up. Surgical and non-surgical therapies were discussed with the parents.Conclusion: Congenital unilateral facial palsy caused by a developmental defect outside the context of a syndrome is rare. A multidisciplinary approach is recommended to differentiate between various causes and to initiate timely treatment.What is Known:• Congenital facial palsy is mostly caused by environmental/external fcators.• However in rare cases it can be developmental defect.What is New:• This paper describes 6 cases of isolated congenital facial palsy related to a developmental defect and presents the largest case series in the literature caused by aplasia/hypoplasia of the facial nerve.• MRI and CT-imaging allow for an assessment of the facial nerve at the root entry zone of the brainstem and along its course through the middle ear or the face. Moreover, they proved to be helpful in differentiating between several causes of congenital facial palsy.

[Congenital facial palsy].

Congenital facial palsy is unilateral or bilateral facial nerve palsy at birth due to genetic or different pathogenic factors. It can be divided into syndromic type and non-syndromic type according to its accompanying symptom. The pathogeny and symptom of each type are different, in part with genetic heterogeneity. Congenital facial palsy cannot recover spontaneously. Different types of congenital facial palsy have different treatment schemes. The treatment is significant to the improvement of life quality and physical and mental development of children with congenital facial palsy.

Neuromodulator for the Treatment of Congenital Unilateral Lower Lip Palsy.

INTRODUCTION:: Congenital unilateral lower lip palsy is an infrequently encountered condition that manifests as lower lip asymmetry during smiling, laughing, and crying. Treatment options are not well characterized. METHODS:: The authors present the case of a 51-year-old woman who was referred for surgical intervention for facial paralysis. Physical examination demonstrated a symmetric face at rest that became asymmetric when smiling. The asymmetry, evident by inappropriate inferior displacement of the lower lip, was secondary to unilateral contraction and presence of the depressor labii inferioris. The depressor anguli oris was symmetric bilaterally. Her presentation was consistent with congenital unilateral lower lip palsy. RESULTS:: Lidocaine was injected into the depressor labii inferioris on the side of the face that demonstrated unilateral presence and contraction. This resulted in symmetry of the smile and lower lip without untoward effect. Onabotulinum toxin A was thereafter injected into the depressor labii inferioris. In-office treatment with botulinum toxin injection resulted in a 4-month improvement in smile symmetry. CONCLUSION:: Chemodenervation is a safe and minimally invasive method to improve smile symmetry and lower lip position in cases of congenital unilateral lower lip palsy.

Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis.

PURPOSE: To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis. METHODS: We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls. RESULTS: Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006-0.0060). CONCLUSION: MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.

Magnetic resonance imaging of developmental facial paresis: a spectrum of complex anomalies.

PURPOSE: Despite its clinical implications, the MRI features of developmental facial paresis (DFP) were described in a few case reports. This study aims to describe MRI features of DFP in relation to the embryological development with a proposed radiological new grading system. METHODS: The clinical records and MRI of the brain and internal auditory canal of 11 children with DFP were retrospectively reviewed. The following sequences were analyzed: axial, oblique sagittal SPACE of the internal auditory canal and brainstem; axial T2, T1WI and coronal T2WI of the brain. The severity of the maldevelopment of the seventh nerve was graded from 0 to 4: 0 = no abnormalities, 1 = unilateral facial nerve hypoplasia, 2 = unilateral facial nerve aplasia, 3 = aplasia or hypoplasia involving facial nerves on both sides, and 4 = facial nerve aplasia or hypoplasia associated with other cranial nerve palsy. RESULTS: Isolated facial nerve palsy was diagnosed in seven patients. It was of grade 1 in five and grade 3 in two. Hypoplasia of the nerve with interrupted course was encountered in two cases. Other associated cranial nerve abnormalities (grade 4) were seen in four patients; two of them were diagnosed previously as Moebius syndrome. In addition to inner ear anomalies, middle and external ear and parotid gland anomalies were described. CONCLUSION: To our knowledge, this is the largest series of patients with DFP that represents a continuum of isolated and combined malformations. Understanding of embryological basis can give insights into the anomalous development of the facial nerve.

Congenital asymmetric crying facies syndrome: A case report.

INTRODUCTION: Congenital asymmetric crying facies (ACF) in newborns is a rare condition usually caused by unilateral agenesis or hypoplasia of the depressor anguli oris muscle on one side of the mouth (symmetric face at rest and asymmetric face while crying), which is often accompanied with other malformations. CASE REPORT: We present a case of a female newborn with nonconsanguineous ethnic Han Chinese parents who presented with 37 minutes of breathlessness and asymmetrical face when crying. A thorough physical examination had been conducted. The patient was diagnosed with aspiration pneumonia and congenital ACF syndrome, accompanied with congenital bilateral anophthalmia, left homolateral auricle dysplasia, malformation in the left-hand thumb, patent ductus arteriosus (PDA), and patent foramen ovale (PFO) and tracheoesophageal fistula. The patient's mother underwent routine fetal sonogram at 25 weeks gestation, which showed major anatomical anomalies in the eyes of the fetus. The mother chose to pregnancy until vaginal delivery. This case is unique because congenital bilateral anophthalmia has not been reported in such patients before. CONCLUSION: Careful physical examination of newborns and genetic testing are important for early diagnosis of neonatal asymmetric crying facies (NACF), especially if ACF is present. Early determination of the etiology and future screenings are very important for the management of this condition. The lower lip on the affected side looks thinner because of the lack of the muscle agenesis, so the use of ultrasound to observe facial muscles and electrodiagnostic testing could be helpful for the differential diagnosis of NACF from congenital facial nerve dysplasia.

Toxina botulínica para tratamento de síndrome do Choro Assimétrico: relato de caso / Botulinum toxin in the treatment of asymmetric crying face syndrome: a case report

Síndrome do choro assimétrico é uma condição congênita secundária à hipoplasia ou ausência do músculo depressor do ângulo da boca. Trata-se de uma condição não tão incomum que pode cursar com assimetria facial ao chorar e sorrir, além de poder estar associadas a outras malformações congênitas. Crianças com essa deformidade podem sofrer dificuldades psicossociais e introversão. O arsenal terapêutico dessa condição já foi estudado e discutido na literatura com ênfase em abordagens cirúrgicas e invasivas. Relatamos aqui um caso de uma criança de 9 anos com essa síndrome, tratada, de forma menos invasiva, com toxina botulínica, com um bom resultado e satisfação.

Asymmetric crying face syndrome is a congenital condition secondary to hypoplasia or absence of the depressor muscle at the mouth angle. It is a common condition that presents with facial asymmetry while crying and smiling and may be associated with other congenital malformations. Children with this deformity may experience psychosocial difficulties and introversion. The therapeutic arsenal of this condition has already been studied and discussed in the literature with an emphasis on surgical and invasive approaches. We report here a case of a 9-year-old child with this syndrome, treated less invasively with botulinum toxin, with good result and satisfaction.

Disgenesia troncoencefálica: más allá del síndrome de Moebius / Brainstem dysgenesis: beyond Moebius syndrome

El termino 'disgenesia troncoencefálica' se aplica a los pacientes que presentan afectación congénita de múltiples pares craneales, hipotonía muscular y signos leves de afectación de la vía piramidal. Este término es ventajoso respecto al uso de epónimos tales como Moebius, Robin, Cogan y Carey-Fineman-Ziter, ya que es menos restrictivo y ofrece un nuevo enfoque para comprender las causas y su patogenia, así como para mejorar el tratamiento de este grupo de alteraciones del desarrollo que afectan exclusiva o predominantemente al tronco del encéfalo. La revisión de la bibliografía y nuestra experiencia muestran que la mayoría de los casos con afectación selectiva del rombencéfalo se deben a lesiones disruptivas prenatales, mientras que en los casos con afectación del mesencéfalo y el cerebelo, así como en los síndromes polimalformativos con afectación destacada del troncoencéfalo, la topografía de las lesiones es más difusa y menos específica, y la causa hereditaria, más probable. Debido a la amplia heterogeneidad fenotípica asociada a la disgenesia troncoencefálica, es esencial realizar una evaluación individualizada y establecer un plan de tratamiento específico. Los programas de rehabilitación deben comenzar poco después del diagnóstico y centrarse en mejorar las habilidades motoras, dotando al paciente de las herramientas necesarias para afrontar las necesidades diarias en función de la morbilidad asociada. Aunque el pronóstico de la disgenesia troncoencefálica secundaria a lesiones disruptivas depende de la localización y la extensión del territorio vascular afectado, en general, el pronóstico de los pacientes con disgenesia troncoencefálica es mejor de lo que las manifestaciones clínicas iniciales harían suponer

Brainstem dysgenesis designates all those patients with congenital dysfunction of cranial nerves and muscle tone due to prenatal lesions or malformations of the brainstem. This generic term has the advantage over the eponyms Moebius 'expanded' or 'unrestricted', Robin, Cogan or Carey-Fineman-Ziter syndromes in that it has a less restrictive view and provides a frame work that enables a systematic approach to diagnosis and research of most developmental disorders involving the brainstem. The review of the literature and our experience shows that infants with a predominant rombencephalic involvement are due to brainstem prenatal disruptive vascular accidents, while cases with midbrain and cerebellar involvement and widespread malformative syndromes have most likely an underlying genetic cause. Due to phenotypic heterogeneity associated with brainstem dysgenesis, it is crucial to evaluate each case individually and to establish a specific therapeutic plan. Intervention programs should start soon after diagnosis and directed to improve functions needed for daily life activities. Even though the prognosis of patients with brainstem dysgenesis due to prenatal destructive lesions depends on the magnitude of the vascular territory involved, in most patients with brainstem dysgenesis, the prognosis is better than the initial clinical manifestations would indicate

Electrophysiological Evaluation of the Facial Muscles in Congenital Unilateral Lower Lip Palsy.

OBJECTIVES: Congenital unilateral lower lip palsy (CULLP) is a congenital facial asymmetry in which one corner of the mouth does not dip downward symmetrically (Kobayashi, 1979). We analyzed the electrophysiological findings in cases of CULLP to understand the facial nerve mechanisms underlying this pathological condition. METHODS: The electrophysiological findings in 20 patients with CULLP including an electroneuronography (ENoG) of the orbicularis oris muscle, nerve excitability test (NET) results, and the blink reflex (BR) were analyzed. RESULTS: Of 21 patients with CULLP, 20 underwent ENoG, 12 underwent a NET, and 14 underwent a BR examination. Nine of 19 patients with CULLP showed higher ENoG amplitude in the affected side than in the unaffected side. In four patients, the ENoG amplitude in the affected side was similar to that in the unaffected side whereas six patients had higher ENoG amplitude in the unaffected side. All patients showed a normal BR response and only one patient had a left-right difference in the NET response in the marginal mandibular branch. NET also demonstrated that the muscular twitch appeared on the lower lip of the affected side. CONCLUSION: These results suggested that in CULLP, each of the facial nerve branches including the marginal mandibular branch appeared to function within normal parameters. The marginal mandibular branch of the facial nerve, which usually innervates the depressor anguli oris and depressor labii inferioris muscles, may innervate adjacent muscles as well, such as the orbicularis oris muscle, during prenatal development.

Estudio clínico, citogenético, molecular y de imagen de los pacientes con síndrome de Moebius del Hospital General 'Dr Manuel Gea González', Ciudad de México / Clinical, cytogenetic, molecular and image study of patients with Mobius syndrome at the General Hospital 'Dr Manuel Gea González', Mexico city

Introducción y Objetivo. El síndrome de Moebius es un trastorno congénito poco frecuente con prevalencia menor del 0.05%, caracterizado por parálisis facial congénita asociada a ausencia de abducción de los ojos por alteraciones del VI y VII nervios craneales, ya sea simétrica o asimétrica. La etiopatogenia cuenta con diferentes hipótesis: genética, vascular y teratógena. Existen pocos reportes en la literatura, y en especial en la latinoamericana, que describan las características clínicas y genéticas de estos pacientes. El presente estudio es el resultado del desarrollo de un equipo multidisciplinario en nuestro centro hospitalario para la descripción del espectro completo de la patología y así poder ofrecer los mejores tratamientos para cada uno de nuestros pacientes. Material y Método. Analizamos 115 pacientes con diagnóstico de síndrome de Moebius en sus 3 presentaciones: Moebius clásico, Moebius incompleto o Moebiuslike. Todos fueron sometidos a exploración física completa por un equipo multidisciplinario formado por ortopedistas, oftalmólogos, otorrinolaringólogos, ortodoncistas, neurólogos, pediatras, genetistas y cirujanos plásticos. Realizamos cariotipos a todos los pacientes para identificar anormalidades estructurales cromosómicas y enviamos muestras al Instituto Nacional de Medicina Genómica (INMeGen) para análisis molecular de cada paciente e identificación de posibles genes involucrados. Resultados. Un total de 52 pacientes (45%) fueron varones y 63 (55%) mujeres. Las manifestaciones clínicas fueron parálisis facial unilateral o bilateral con involucro de la abducción de los ojos en el 100%, asociada con estrabismo en el 62.6%, pie equino varo en el 46.1%, sindactilia simple 15.7%, paladar hendido 17.4%, micrognatia 17.4%, y síndrome de Poland 9.6%, entre otras manifestaciones. El análisis citogenético reportó 114 cariotipos de características estructurales normales y 1 solo caso de translocación recíproca balanceada entre el cromosoma 4 y 10. Dieciséis casos se asociaron a consumo materno de misoprostol en el primer trimestre del embarazo. El análisis molecular no se pudo concretar debido a falta de recursos materiales del INMeGen. Conclusiones. Hasta la fecha, y hasta donde hemos podido comprobar, esta es la cohorte de pacientes con síndrome de Moebius más grande reportada a nivel mundial en un solo centro hospitalario. La variabilidad de las presentaciones clínicas justifica el manejo por un equipo multidisciplinario tanto para el paciente como para los familiares. Este estudio abre las puertas para un campo de investigación mayor que nos pueda llevar a entender mejor la fisiopatología, intentar estableces causalidad y por lo tanto poder ofrecer mejores tratamientos, integrales y reproducibles (AU)

Background and Objective. Möbius syndrome is a rare congenital disease characterized by facial paralysis associated with an absence of abduction of the eyes for abnormalities in VI and VII cranial nerves. The pathogenesis has different hypothesis that include genetic, vascular and teratogenic causes. There are few reports in the literature and especially in Latin America to describe the clinical and genetic characteristics of these patients. The current study is the result of a multidisciplinary team developed in our center to describe the wide spectrum of the disease and offer the best treatment options to each of our patients. Methods. We analyzed 115 patients with the diagnosis of Möbius syndrome in its 3 presentations. All patients underwent a complete clinical examination by a multidisciplinary team formed by orthopedist, ophthalmologist, otolaryngologist, orthodontist, neurologist, plastic surgeon, pediatrician and geneticist. They underwent CTG banded karyotype to identify structural chromosome abnormalities. Results. Fifty two patients (45%) patients were male and 63 (55%) female. Clinical manifestations were found with unilateral or bilateral facial paralysis with VI nerve involvement in 100% of patients, associated with strabismus in 62.6%, 46.1% clubfoot, simple syndactyly 15.7%, 17.4% cleft palate, micrognathia 17.4%, Poland syndrome 9.6%, among others. Cytogenetic analysis showed normal karyotype in 114 patients and a reciprocal translocation between chromosome 4 and 10 in 1 patient. Sixteen cases of reported intake of misoprostol during the first trimester. Conclusions. As far as we know, this study is the largest global cohort reported in a single hospital of patients with Möbius syndrome. Variability of the clinical presentation justifies the management of these patients is a multidisciplinary team. This study opens the door for new studies that allow us to understand the pathophysiology of this disease and its response to different treatments (AU)

A TUBB6 mutation is associated with autosomal dominant non-progressive congenital facial palsy, bilateral ptosis and velopharyngeal dysfunction.

Congenital cranial dysinnervation disorders (CCDDs) comprise a heterogeneous spectrum of diseases characterized by congenital, non-progressive impairment of eye, eyelid and/or facial movements including Möbius syndrome, Duane retraction syndrome, congenital ptosis, and congenital fibrosis of the extraocular muscles. Over the last 20 years, several CCDDs have been identified as neurodevelopmental disorders that are caused by mutations of genes involved in brain and cranial nerve development, e.g. KIF21A and TUBB3 that each plays a pivotal role for microtubule function. In a five-generation pedigree, we identified a heterozygous mutation of TUBB6, a gene encoding a class V tubulin which has not been linked to a human hereditary disease so far. The missense mutation (p.Phe394Ser) affects an amino acid residue highly conserved in evolution, and co-segregates with a phenotype characterized by congenital non-progressive bilateral facial palsy and congenital velopharyngeal dysfunction presenting with varying degrees of hypomimia, rhinophonia, impaired gag reflex and bilateral ptosis. Expression of the mutated protein in yeast led to an impaired viability compared to wildtype cells when exposed to the microtubule-poison benomyl. Our findings enlarge the spectrum of tubulinopathies and emphasize that mutations of TUBB6 should be considered in patients with congenital non-progressive facial palsy. Further studies are needed to verify whether this phenotype is indeed part of the CCDD spectrum.

An exome sequencing study of Moebius syndrome including atypical cases reveals an individual with CFEOM3A and a TUBB3 mutation.

Moebius syndrome is characterized by congenital unilateral or bilateral facial and abducens nerve palsies (sixth and seventh cranial nerves) causing facial weakness, feeding difficulties, and restricted ocular movements. Abnormalities of the chest wall such as Poland anomaly and variable limb defects are frequently associated with this syndrome. Most cases are isolated; however, rare families with autosomal dominant transmission with incomplete penetrance and variable expressivity have been described. The genetic basis of this condition remains unknown. In a cohort study of nine individuals suspected to have Moebius syndrome (six typical, three atypical), we performed whole-exome sequencing to try to identify a commonly mutated gene. Although no such gene was identified and we did not find mutations in PLXND1 and REV3L, we found a de novo heterozygous mutation, p.E410K, in the gene encoding tubulin beta 3 class III (TUBB3), in an individual with atypical Moebius syndrome. This individual was diagnosed with near-complete ophthalmoplegia, agenesis of the corpus callosum, and absence of the septum pellucidum. No substantial limb abnormalities were noted. Mutations in TUBB3 have been associated with complex cortical dysplasia and other brain malformations and congenital fibrosis of extraocular muscles type 3A (CFEOM3A). Our report highlights the overlap of genetic etiology and clinical differences between CFEOM and Moebius syndrome and describes our approach to identifying candidate genes for typical and atypical Moebius syndrome.