Physiopathologic Bases of Moebius Syndrome: Combining Genetic, Vascular, and Teratogenic Theories.

Moebius syndrome (MBS) is a congenital cranial dysinnervation disorder (CCDD) characterized by a bilateral palsy of abducens and facial cranial nerves, which may coexist with other cranial nerves palsies, mostly those found in the dorsal pons and medulla oblongata. MBS is considered a "rare" disease, occurring in only 1:50,000 to 1:500,000 live births, with no gender predominance. Three independent theories have been described to define its etiology: the vascular theory, which talks about a transient blood flow disruption; the genetic theory, which takes place due to mutations related to the facial motor nucleus neurodevelopment; and last, the teratogenic theory, associated with the consumption of agents such as misoprostol during the first trimester of pregnancy. Since the literature has suggested the existence of these theories independently, this review proposes establishing a theory by matching the MBS molecular bases. This review aims to associate the three etiopathogenic theories at a molecular level, thus submitting a combined postulation. MBS is most likely an underdiagnosed disease due to its low prevalence and challenging diagnosis. Researching other elements that may play a key role in the pathogenesis is essential. It is common to assume the difficulty that patients with MBS have in leading an everyday social life. Research by means of PubMed and Google Scholar databases was carried out, same in which 94 articles were collected by using keywords with the likes of "Moebius syndrome," "PLXND1 mutations," "REV3L mutations," "vascular disruption AND teratogens," and "congenital facial nerve palsy." No exclusion criteria were applied.

Clinical and genetic characteristics of Chinese patients with congenital cranial dysinnervation disorders.

BACKGROUND: Congenital cranial dysinnervation disorders (CCDDs) are a group of diseases with high clinical and genetic heterogeneity. Clinical examinations combined with Magnetic resonance imaging (MRI) and whole exome sequencing (WES) were performed to reveal the phenotypic and genotypic characteristics in a cohort of Chinese CCDDs patients. RESULTS: A total of 122 CCDDs patients from 96 families were enrolled. All patients showed restrictive eye movements, and 46 patients from 46 families (47.9%, 46/96) were accompanied by multiple congenital malformations. Multi-positional high-resolution MRI was performed in 94 patients from 88 families, of which, all patients had hypoplasia of the cranial nerves except HGPPS patients and 15 patients from 15 families (17.0%,15/88) were accompanied by other craniocerebral malformations. WES was performed in 122 CCDDs patients. Ten pathogenic variants were detected in KIF21A, TUBB3, and CHN1 genes in 43 families. Three variants were unreported, including KIF21A (c.1064T > C, p.F355S), TUBB3 (c.232T > A, p.S78T) and CHN1 (c.650A > G, p.H217R). Of the 43 probands harboring pathogenic variants, 42 were diagnosed with Congenital Fibrosis of Extraocular Muscles (CFEOM) and one was Duane Retraction Syndrome (DRS). No definite pathogenic variants in known candidate genes of CCDDs were found in sporadic DRS, Möbius Syndrome (MBS) and Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) patients. The CFEOM patients harboring R380C, E410K and R262H variants in TUBB3 gene and F355S variant in KIF21A gene exhibited syndromic phenotypes. CONCLUSIONS: This study broadened the phenotypic and genotypic spectrums of CCDDs, and it was the largest clinical and genetic investigation for CCDDs patients from China. KIF21A and TUBB3 were the common pathogenic genes in Chinese CFEOM. MRI coupled with WES can provide a supportive diagnosis in patients with clinically suspected CCDDs.

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

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

Difficult intubation and postoperative aspiration pneumonia associated with Moebius syndrome: a case report.

BACKGROUND: Moebius syndrome is a rare congenital disorder characterized by non-progressive palsy of the abducens (VI) and facial (VII) cranial nerves. Its common features include dysfunctions associated with other cranial nerves, orofacial abnormalities, skeletal muscle hypotonia, and other systemic disorders of differing severities. There are several concerns in the perioperative management of patients with Moebius syndrome. CASE PRESENTATION: We present a report on the management of general anesthesia of a 14-year-old male patient with Moebius syndrome who was scheduled for mandibular cystectomy. The patient was diagnosed with Moebius syndrome at the age of 7 years based on his clinical manifestations of nerve palsy since birth and cranial nerve palsy of the trigeminal (V), facial (VII), glossopharyngeal (IX), vagus (X), and sublingual nerves (XII). The patient's oral morphological abnormalities made intubation difficult. He also experienced dysphagia and aspiration pneumonia on a daily basis. Oral secretions were frequently suctioned postoperatively. However, after discharge, the patient developed aspiration pneumonia and was readmitted to the hospital. CONCLUSIONS: The main problem arising when administering general anesthesia to patients with this syndrome is difficult airway management. The oral abnormalities in these patients, such as small jaw and extreme dental stenosis, make mask ventilation and intubation difficult. Furthermore, this syndrome often involves respiratory impairment and dysphagia due to cerebral nerve palsy, so there is a high risk of postoperative respiratory complications. Since multiple organs are affected in patients with Moebius syndrome, appropriate perioperative management strategies must be prepared for these patients.

Neurogenic bladder as a lurking complication in Moebius syndrome.

Moebius syndrome (MBS) is a congenital disorder characterized by facial and abducens palsy, sometimes accompanied with other cranial nerve palsies and comorbid conditions. Anatomical anomalies of the brainstem are assumed to be major etiologies of MBS. Its phenotypic presentation can be variable. We report a female patient with MBS who presented with neurogenic bladder (NB). She was born via normal vaginal delivery. At birth, she showed bilateral abducens palsy and right facial palsy. We diagnosed MBS by cranial computed tomography scan and magnetic resonance imaging. She had recurrent urinary tract infection. Hydronephrosis was noted on ultrasonography and bilateral vesicoureteral reflux (grade 5) on voiding cystourethrography. Urodynamic investigation showed detrusor overactivity and detrusor-sphincter dyssynergia, which follow the pattern of NB resulting from infrapontine-suprasacral lesions. Patients with MBS have lower brainstem dysfunction, and accordingly we should be aware of NB.

Impact of Adding Augmented Superior Rectus Transpositions to Medial Rectus Muscle Recessions When Treating Esotropic Moebius Syndrome.

PURPOSE: To describe outcomes after treatment of Moebius syndrome (MBS) esotropia by adjustable bilateral medial rectus recession (BMR) with and without augmented superior rectus transposition (SRT). DESIGN: Retrospective case series. METHODS: Patients meeting 2014 diagnostic criteria for MBS and treated at Boston Children's Hospital between 2003 and 2019 were identified via billing records and chart review. Visual acuity, sensorimotor evaluations, strabismus procedures, and other clinical features were recorded. Surgical outcomes for patients treated with strabismus surgery (excluding those with prior surgery elsewhere) were evaluated. The primary outcome measure was postoperative alignment comparing treatment by adjustable BMR vs adjustable BMR+SRT. RESULTS: A total of 20 patients had MBS, and 12 of these (60%) were male. Fifteen patients (75%) had primary position esotropia, and all had bilateral abduction deficit. Eight of 20 patients met inclusion criteria for primary strabismus surgery outcome. Five had undergone adjustable BMR ranging from 4.5 to 6.5 mm. Three had undergone adjustable BMR+SRT, all with 4-mm medial rectus muscle recessions. Mean preoperative esotropia before treatment by BMR was 39.5 PD (± 15 PD) with mean postoperative esotropia 9 PD (± 7.9 PD) at 6 months. Mean preoperative esotropia before treatment by BMR+SRT was 70.8 PD (± 5.9 PD) with mean postoperative esotropia 2.5 PD (± 3.5 PD) at 6 months. Significantly greater reduction in esotropia resulted from BMR+SRT than from BMR (P = .036). CONCLUSIONS: BMR proved sufficient to treat esotropia <50 PD and BMR+SRT for greater esotropia in patients with MBS-associated abduction limitation.

A New Neurorehabilitative Postsurgery Intervention for Facial Palsy Based on Smile Observation and Hand-Mouth Motor Synergies.

Objective: To perform a preliminary test of a new rehabilitation treatment (FIT-SAT), based on mirror mechanisms, for gracile muscles after smile surgery. Method: A pre- and postsurgery longitudinal design was adopted to study the efficacy of FIT-SAT. Four patients with bilateral facial nerve paralysis (Moebius syndrome) were included. They underwent two surgeries with free muscle transfers, one year apart from each other. The side of the face first operated on was rehabilitated with the traditional treatment, while the second side was rehabilitated with FIT-SAT. The FIT-SAT treatment includes video clips of an actor performing a unilateral or a bilateral smile to be imitated (FIT condition). In addition to this, while smiling, the participants close their hand in order to exploit the overlapped cortical motor representation of the hand and the mouth, which may facilitate the synergistic activity of the two effectors during the early phases of recruitment of the transplanted muscles (SAT). The treatment was also aimed at avoiding undesired movements such as teeth grinding. Discussion. Results support FIT-SAT as a viable alternative for smile rehabilitation after free muscle transfer. We propose that the treatment potentiates the effect of smile observation by activating the same neural structures responsible for the execution of the smile and therefore by facilitating its production. Closing of the hand induces cortical recruitment of hand motor neurons, recruiting the transplanted muscles, and reducing the risk of associating other unwanted movements such as teeth clenching to the smile movements.

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.

Diagnosis and treatment of speech disorders in children with Moebius syndrome.

BACKGROUND: Moebius syndrome (MS) is characterized by congenital bilateral paralysis of the facial and abducens nerves. Clinical features include feeding problems, dysarthria, dysphagia, sialorrhea, strabismus, and lack of facial expression. Patients with MS frequently present with dysphagia during infancy. Further on during childhood a severe speech disorder is a common feature. However, articulation deficits in patients with MS are scarcely reported in the related scientific literature. OBJECTIVE: The aim of this study is to describe speech deviations, intelligibility and sialorrhea in patients with MS. MATERIAL AND METHODS: Eighty-seven patients with MS were prospectively studied. Age ranged from 4 to 18 years. A complete Speech and Language Pathology (SLP) evaluation was performed in all cases. The evaluation focused on articulation placement, sialorrhea and intelligibility of speech. RESULTS: Sialorrhea was detected in 23% of the patients. Abnormal articulation placement of bilabial phonemes was observed in 68% of the patients. Another 50% of the patients presented with articulation placement errors in other phonemes. Intelligibility was classified as adequate in 18% of the cases. Mildly affected intelligibility was found in 51% of the patients. Speech was considered moderately unintelligible in 20% of the cases. Unintelligible speech was found in 11% of the patients. CONCLUSIONS: From the results of this prospective study it can be concluded that a high percentage of patients with MS are at high risk of presenting with moderate to severe speech disorders. Thus, an early SLP intervention should be provided for this population in order to enhance speech development and reducing the risk of severe oral communication impairments.

Carey-Fineman-Ziter Syndrome: A MYMK-Related Myopathy Mimicking Brainstem Dysgenesis.

Carey-Fineman-Ziter syndrome is a congenital myopathy associated with mutations in the MYMK gene. It is clinically defined by the combination of hypotonia, Moebius-Robin sequence, facial anomalies and motor delay. Historically it was considered a brainstem dysgenesis syndrome. We provide detailed information of a Spanish boy with compound heterozygous variants in MYMK gene. A muscle biopsy performed as a toddler only disclosed minimal changes, but muscle MRI showed severe fatty infiltration of gluteus muscles and to a lesser extent in adductors magnus, sartorius and soleus muscles. Clinical course is fairly static, but the identification of new well characterized genetic cases will help to delineate the complete phenotype.

Mobius syndrome and obsessive compulsive disorder: a case report.

BACKGROUND: Mobius syndrome is characterized by a bilateral congenital paralysis of the facial and abducens nerves which leaves the subject with an expressionless "mask-like" face. SUBJECTS AND METHODS: Based on a literature review and a case discussion of an adult patient with Mobius syndrome and obsessive-compulsive disorder, initially undiagnosed and confused with a psychotic disorder, we will discuss the influence of Mobius syndrome in psychiatric evaluations. RESULTS: The lack of facial expressiveness and non-verbal emotional interactions may influence psychiatric evaluations and result in misdiagnosis and the inappropriate prescribing of antipsychotics. In the case analysis, we also observed other associated malformations such as renal atrophy, a bicuspid aortic valve and mitral valve prolapse. CONCLUSION: We feel that educating the patient about the communicative consequences of impaired facial expressions and facial interactions is a necessary prerequisite for any psychiatric or psychological evaluation in subjects with Mobius syndrome. We also recommend using caution when prescribing antipsychotics in patients with Mobius syndrome given the motor side effects secondary to a potentially pre-existing hypotonia.

Möbius syndrome associated with obesity and precocious puberty.

Möbius syndrome is a neurological disorder involving underdevelopment of the sixth and seventh cranial nerves. Multiple associations have been described including dysfunction of other cranial nerves, limb abnormalities and hypogonadotrophic hypogonadism causing delayed puberty. We present the second reported case of Möbius syndrome associated with obesity and with precocious puberty. These features may be secondary to dysregulation of the hypothalamic-pituitary axis. We highlight the need to consider extraocular symptoms in these patients and for close liaison with physicians in their management.

Síndrome de Moebius incompleto. Presentación de un caso clínico / Incomplete Moebius syndrome. Clinical case presentation

RESUMEN El síndrome de Moebius es un trastorno polimalformativo no progresivo que se caracteriza por parálisis facial congénita. Se define como una "parálisis congénita de los núcleos de los pares craneales VI y VII, cuyo espectro clínico es variable y se asocia a múltiples malformaciones óseas y musculares. Es poco frecuente y de etiología vascular, genética o multifactorial. El trabajo, basándose en los fundamentos teóricos más actualizados, pretendió describir las manifestaciones clínicas del síndrome de Moebius y su posible etiología, a propósito de un caso. Se trató de un paciente de 11 años de edad, que al nacimiento presentó asimetría facial, desviación de la comisura labial hacia la izquierda, boca semiabierta, lagrimeo constante y pabellón auricular derecho malformado. Por ser una entidad clínica poco conocida, se expuso el presente caso, portador de un síndrome de Moebius incompleto de causa vascular y multifactorial (AU).

ABSTRACT Moebius syndrome is a non-progressive poli-formative disorder characterized by facial congenital paralysis. It is defined as a congenital paralysis of the VI and VII cranial nerves nuclei, the clinical spectrum of which is variable and associated to several bone and muscular malformations. It is few frequent and has vascular, genetic or multifactorial etiology. This work, based on more updated theoretical fundaments, pretended to describe the clinical manifestations of the Moebius syndrome and its possible etiology on the purpose of a case. It is the case of a patient, aged 11 years, who presented facial asymmetry, lips commissure deviation to the left, semi-opened mouth, constant lagrimeo and deformed right auricular pavilion (pabellon auricular). Because it is a little known clinical entity, this case of a patient having an incomplete Moebius syndrome of vascular and multifactorial cause was presented (AU).

Evaluation of Moebius syndrome with hand manifestations.

Moebius Syndrome (MS) is characterized by congenital paralysis of the 6th and 7th cranial nerves, sometimes combined with deficits in cranial nerves and with limb anomalies. We reported that identifying common upper extremity orthopedic manifestations of this syndrome would asist physicians who care for affected patients to promtly establish a dignosis and treatment plan. Our internal medical record system was queried and a keyword search for "Möbius/Moebius Syndrome" was conducted. The clinical data collected for each patient consisted of age at diagnosis, date of first and date of final follow-up, treatment type, treatment duration, and complications from treatment. Clinical data collected for hand and upper limb deformities included effected side, diagnosis, surgical procedures, and any post-op complications. All data was collected from radiographic images including X-ray, ultrasound, CT, and MRI imaging, and clinical, physical therapy, orthotics, and operative notes. As regards older reports, it is realized that abnormalities in upper extremity in MS is associated with PS. We wish that this descriptive study will be helpful for those physicians who encounter this rare disease, in terms of identifying and providing timely treatment for associated upper extremity abnormalities and for assisting in counseling patients.

Möbius syndrome with cardiac rhabdomyomas.

BACKGROUND: Möbius syndrome is a rare congenital condition which presents not merely with 6th and 7th nerve palsies, but involves gaze paresis associated with craniofacial, limb, and other abnormalities. Heterogeneity is well known in patients with Möbius syndrome and rather than being of familial inheritance based on rare cases, it is much more recognized as a sporadic syndrome. We report an infant with features of congenital Möbius syndrome associated with cardiac rhabdomyomas in the absence of tuberous sclerosis. MATERIALS AND METHODS: Observational case report of an infant seen at a tertiary academic center with genetic testing, ophthalmic, neurological, and cardiac clinical examination and imaging. RESULTS: A newborn baby boy at birth was seen with multiple congenital craniofacial malformations, and respiratory distress. He was noted to have micrognathia, retrognathia, wide nasal bridge, low set ears, high arched palate, nonreducing bilateral talipes equinovarus and bilateral large angle esotropia with -4 abduction deficit and facial palsy, findings suggestive of Möbius Syndrome. MRI of the brain was unremarkable except for syringomyelia in the cervical spine. Echocardiography showed two cardiac rhabdomyomas in the right ventricle and ulltrasound of the abdomen showed mild right hydroneprosis. Cytogenetics revealed segmental loss at 21q21.2. Testing for tuberous sclerosis was negative for deletion or duplications of genes TSC1 and TSC2. CONCLUSION: This case highlights the rare co-occurrence of cardiac rhabdomyomas with Möbius syndrome and new segmental loss at 21q21.2 on genetic testing. Findings could indicate not a "suggestion of Möbius", but rather the syndrome itself in association with cardiac defects.

Morphological changes in support mechanism of superficial face layers in Moebius syndrome.

Moebius syndrome, also called congenital facial paralysis is a rare neurological disease, whose etiology is not fully elucidated. It affects especially facial and oculomotor cranial nerves and its clinical feature is peripheral facial paralysis. The objective of the study is to highlight the anatomical and functional changes in the Moebius syndrome and establish certain criteria that should be the basis for reparative surgery in this disease. For this purpose, we used a group of six patients diagnosed with this pathology, in whom we pursued functional anatomical and histological changes of the superficial layers of the face that we have grouped in terms of their clinical impact. All the data obtained were centralized in order to assess anatomical functional changes occurring after evolution in time of lesions caused by Moebius syndrome. The results of the study led us to conclude that the face is made up of three main regions - median, medial and lateral -, which behave differently both in atresia of the facial nerve and in healthy individuals. This has an important echo on the way we emphasized the functional anatomy of superficial layers of the face and in surgery.

Clinical correlation of imaging findings in congenital cranial dysinnervation disorders involving abducens nerve.

PURPOSE: High-resolution magnetic resonance imaging (MRI) of intracranial parts of sixth nerve and seventh nerve and the extraocular muscles (EOMs) in orbit to correlate the clinical characteristics in patients with two special forms of strabismus in congenital cranial dysinnervation disorders which are Duane's retraction syndrome (DRS) and Mobius syndrome. MATERIALS AND METHODS: Morphological analysis by 3T MRI of orbit (using surface coils) and brain (using 32 channel head coil) was performed on 6 patients with clinical DRS (1 bilateral), 2 cases with Mobius syndrome, and 1 case with congenital sixth nerve palsy. These were compared with findings in five controls. RESULTS: We observed absence/hypoplasia of sixth nerve in five out of seven eyes with DRS (71.42%), anomalous course in one eye, sixth and seventh nerve absence/hypoplasia in affected eyes with Mobius syndrome and bilateral absence/hypoplasia of the sixth nerve in congenital sixth nerve palsy. For EOMs we calculated maximum diameter, area, and circumference of muscles using Osirix software, and noticed significant hypoplasia of lateral rectus in comparison to controls (P < 0.001). CONCLUSIONS: MRI gives useful information regarding confirmation of clinical diagnosis and its neurological anomalies in complex cases and helps to plan tailor made surgical management.