[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.

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.

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.

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.

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.

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.

Homozygous HOXB1 loss-of-function mutation in a large family with hereditary congenital facial paresis.

Hereditary congenital facial paresis (HCFP) belongs to the congenital cranial dysinnervation disorders. HCFP is characterized by the isolated dysfunction of the seventh cranial nerve and can be associated with hearing loss, strabismus, and orofacial anomalies. Möbius syndrome shares facial palsy with HCFP, but is additionally characterized by limited abduction of the eye(s). Genetic heterogeneity has been documented for HCFP as one locus mapped to chromosome 3q21-q22 (HCFP1) and a second to 10q21.3-q22.1 (HCFP2). The only known causative gene for HCFP is HOXB1 (17q21; HCFP3), encoding a homeodomain-containing transcription factor of the HOX gene family, which are master regulators of early developmental processes. The previously reported HOXB1 mutations change arginine 207 to another residue in the homeodomain and alter binding capacity of HOXB1 for transcriptional co-regulators and DNA. We performed whole exome sequencing in HCFP-affected individuals of a large consanguineous Moroccan family. The homozygous nonsense variant c.66C>G/p.(Tyr22*) in HOXB1 was identified in the four patients with HCFP and ear malformations, while healthy family members carried the mutation in the heterozygous state. This is the first disease-associated HOXB1 mutation with a likely loss-of-function effect suggesting that all HOXB1 variants reported so far also have severe impact on activity of this transcriptional regulator. © 2016 Wiley Periodicals, Inc.

Amblyopia Associated with Congenital Facial Nerve Paralysis.

The association between congenital facial paralysis and visual development has not been thoroughly studied. Of 27 pediatric cases of congenital facial paralysis, we identified 3 patients who developed amblyopia, a visual acuity decrease caused by abnormal visual development, as comorbidity. These 3 patients had facial paralysis in the periocular region and developed amblyopia on the paralyzed side. They started treatment by wearing an eye patch immediately after diagnosis and before the critical visual developmental period; all patients responded to the treatment. Our findings suggest that the incidence of amblyopia in the cases of congenital facial paralysis, particularly the paralysis in the periocular region, is higher than that in the general pediatric population. Interestingly, 2 of the 3 patients developed anisometropic amblyopia due to the hyperopia of the affected eye, implying that the periocular facial paralysis may have affected the refraction of the eye through yet unspecified mechanisms. Therefore, the physicians who manage facial paralysis should keep this pathology in mind, and when they see pediatric patients with congenital facial paralysis involving the periocular region, they should consult an ophthalmologist as soon as possible.

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.

The natural history of Möbius syndrome in a 32-year-old man.

Möbius syndrome (OMIM#157900) is an extremely rare congenital entity involving bilateral or unilateral palsy of the facial nerve, usually with dysfunction of other cranial nerves (second, third, fifth, sixth, ninth, tenth and twelfth). It was estimated that Möbius syndrome occurs in 1 of 50 000 live births. The aetiology and the pathogenesis of the syndrome remain unknown. The majority of published cases were sporadic. We report on the natural history of a 32-year-old man with de novo Möbius syndrome. The diagnosis was established at the age of 9 months due to partial bilateral facial and abducent nerve palsy. Additionally, the patient demonstrated failure to thrive during infancy and childhood, many dysmorphic features, lower limb anomalies, and hypogonadism in adulthood, but his intelligence was in the normal range. The low quality of life of the patient with Möbius syndrome is emphasized.

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.

Facial palsy in children: emergency department management and outcome.

OBJECTIVE: To describe the characteristics of children who present to an emergency department (ED) with facial palsy and determine the association of outcome with etiology, degree of initial paralysis, and ED management. METHODS: This was a retrospective cohort study of children who presented to an ED with facial nerve paralysis (FNP). RESULTS: There were 85 patients with a mean age of 8.0 (SD, 6.1) years; 60% (n = 51) of the patients were male, and 65.9% (n = 56) were admitted to the hospital. Bell palsy (50.6%) was the most common etiology followed by infectious (22.4%), traumatic (16.5%), congenital (7.1%), and neoplastic etiologies (3.5%). Patients with Bell palsy had shorter recovery times (P = 0.049), and traumatic cases required a longer time for recovery (P = 0.016). Acute otitis media (AOM)-related pediatric FNP had shorter recovery times than non-AOM-related cases (P = 0.005) in infectious group. Patients given steroid therapy did not have a shorter recovery time (P = 0.237) or a better recovery (P = 0.269). There was no difference in recovery rate of pediatric patients with Bell palsy between hospitalization or not (P = 0.952). CONCLUSION: Bell palsy, infection, and trauma were most common etiologies of pediatric FNP. Recovery times were shorter in pediatric patients with Bell palsy and AOM-related FNP, whereas recovery took longer in traumatic cases. Steroid therapy did not seem beneficial for pediatric FNP. Hospitalization is not indicated for pediatric patients with Bell 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.

Toward shortening interoperation period in two-stage cross facial nerve graft with muscle transfer.

Cross facial nerve graft with free muscle transfer is a well-accepted method to deal with the long-standing facial paralysis, which is usually carried out in 2 separate operations including the nerve graft in first operation followed by a muscle transfer 10 to 12 months later. However, delayed rehabilitation of the nerve graft because of its long length leads to considerable interval between first and second operations. Nine patients with long-standing unilateral facial paralysis underwent 2-stage cross facial nerve graft with some modifications in techniques. In this new technique, by placing the end of the nerve graft in nasolabial fold in the first stage, we used shorter nerve grafts and reduced the interval between operations from 3.5 to 5 months. We believe that by using shorter nerve grafts in this technique, we can perform second-stage operation pretty earlier, and placing the end of nerve graft in nasolabial fold reduces the risk of nerve graft traumatization in preauricular dissection during the second stage.

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.

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.