Hemimegalencephaly is a rare central nervous system disorder of neuronal cell lineage, proliferation, maturation, and migration characterized by in utero
Aug. 24, 2021
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This article includes discussion of Mobius syndrome, congenital abducens-facial paralysis, congenital facial diplegia syndrome, congenital facial palsy syndrome, and congenital oculofacial paralysis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Mobius syndrome is characterized by congenital partial or complete facial diplegia, often accompanied by other cranial nerve palsies and associated with other malformations of the limbs and orofacial structures. These features are observed in the newborn period, and modes of inheritance have been varied. In this update, the author incorporates recent clinical experiences with Mobius syndrome patients, including additional characteristics and syndromes associated with this entity.
• Mobius syndrome, which is characterized by congenital facial diplegia with cranial nerve palsies, exists as a heterogeneous clinical spectrum with many associated malformative lesions.
• To fulfill minimal diagnostic criteria for Mobius syndrome, there must be congenital, nonprogressive facial palsy accompanied by ocular abduction deficits; a newer classification scheme for Mobius syndrome is based on ocular motor phenotypes.
• Numerous behavioral manifestations have been observed in association with Mobius syndrome, including cataplexy, poor impulse control, and aggression.
• The etiology of Mobius syndrome is multifactorial, with both genetic implications (chromosomes 1, 2 10, 13) and intrauterine environmental factors (ischemia, infection); misoprostol use during pregnancy specifically conveys an increased risk to the fetus.
• Management strategies for Mobius syndrome rest with surgical correction of oral-facial abnormalities, with the objective of optimizing function. Timing of surgical intervention may play a crucial role in some patients. The possibility of vascular alterations such as facial artery agenesis in congenital facial palsy should be considered in preoperative planning. Management of Mobius syndrome is of interest to both medical and dental professionals, with advocacy for early rehabilitation to enhance recovery of function.
Mobius syndrome, defined as congenital facial diplegia with restriction of lateral eye movements, was first described by von Graefe in 1880 (99). Mobius, in his review of cranial nerve palsies in children, established 6 groups where sixth and seventh nerve palsies occurring together were incorporated as 1 group (61; 62). Henderson, in 1939, reviewed the clinical manifestations in 61 cases of congenital facial diplegia in which there were 45 cases of abducens palsies, 15 cases of external ophthalmoplegia, 6 cases with ptosis, 18 cases with involvement of the tongue, 19 cases with clubfeet, 13 cases with other brachial malformations, 8 cases with pectoralis muscle defects, and 6 cases with mental defect (34). Henderson’s review incorporated all of the essential features of Mobius syndrome: (1) facial diplegia with other cranial nerve palsies, (2) malformations, particularly of the limbs, and (3) mental retardation with an incidence of 10%. Other clinical features have been described in association with Mobius syndrome, including facioscapulohumeral muscular dystrophy (46), upper labial deficiency (74), cataplexy (90), and poor impulse control with exhibitionism and aggression (33). The clustering of various craniofacial, musculoskeletal, and cardiac malformations as well as the mental retardation commonly observed in patients manifesting this syndrome has suggested that the entity exists along a heterogeneous spectrum. This gives rise to such terms as “Mobius-like syndrome” and “Mobius sequence” (68; 81), which are commonly encountered in the medical literature.
Mobius syndrome is characterized by congenital partial or complete facial diplegia, often accompanied by other cranial nerve palsies and associated with other malformations of the limbs and orofacial structures. The facial palsy is typically noted in the newborn period due to difficulty with nursing and incomplete closure of the eyes while sleeping. Later, the inability to smile or the lack of movement while crying attracts concern. The facies are mask-like with inability to close the mouth and drooling of saliva, a troublesome symptom, especially in older individuals. Speech is indistinct, with difficulty making labial sounds, thus affecting intelligibility (79). Upper labial deficiency was recognized as a feature of Mobius syndrome that had previously been unreported (74).
The distribution of the facial palsy is often bilateral and incomplete (34; 37). It is accompanied by paralysis of the abducens nerve, with inability to abduct the eye, as well as of the oculomotor nerve. The hypoglossal nerve may also be involved, in which case, it is always accompanied by sixth nerve palsy (34; 49). Although the distribution of involvement is typically bilateral, 2 cases of ipsilateral unilateral palatal weakness have been described, with investigations failing to reveal a specific etiology (40).
Limb and craniofacial abnormalities are frequent (59). Children with Mobius syndrome may have talipes equinovarus (49), and absence of the sternal head of the pectoralis muscle accompanied by hand malformations (Poland anomaly) is frequently seen. Other limb defects that have been reported include syndactylism, hypoplasia, and absence of digits. Craniofacial features have included epicanthus, external ear anomalies, bifid uvula, cleft palate, micrognathia, and, rarely, other branchial muscle defects (24). Global hypotonia, giving rise to symptoms suggestive of a severe infantile form of a congenital muscular disorder, may also be the presenting manifestation (38).
A classification and grading system has been proposed for Mobius syndrome to facilitate categorization and comparison of Mobius phenotypes for the purposes of management and study outcome reporting. Referred to as CLUFT, this system grades the anatomic extent of cranial nerve deficits and musculoskeletal abnormalities, specifically evaluating the following: cranial nerves, lower limb, upper limb, face, and thorax (02). Other studies have also defined and classified Mobius syndrome into 2 distinct neurophysiologic phenotypes. In 1 phenotype, patients have increased facial distal motor latencies and poor recruitment of small and polyphasic motor unit action potentials. The second phenotype is characterized by normal facial distal motor latencies and neuropathic motor unit action potentials (21).
In addition, previously 3 specific patterns of alterations in ocular motility were described (20). One pattern (pattern A) consists of orthotopia in primary position, with a complete defect in abduction and adduction movements. A second pattern (pattern B) is characterized by large-angle esotropia and crossed fixation, with a relative sparing of convergence and adduction. In the third pattern (pattern C), which is the most infrequent, patients demonstrate large-angle exotropia in primary position, with torticollis, absence of convergence, and vertical eye misalignment.
A newer classification scheme based on ocular motor phenotype has been presented (73). The first most common pattern, referred to as pattern 1, involves bilateral horizontal gaze palsy with intact vertical range. Pattern 2 is characterized by bilateral horizontal gaze palsy with variable vertical limitations. The third pattern (pattern 3), which is rare, involves abduction deficits. It is proposed that patients with full ocular motility range, or pattern 4, do not meet the minimal criteria for the diagnosis of Mobius syndrome. Standardized ophthalmic examination for Mobius syndrome minimum diagnostic criteria (MDC), along with genetic testing for confirmation, was conducted in a large group, prospective observational study (55). The reliance on facial palsy alone, without ocular motility testing, may result in a misdiagnosis of Mobius syndrome.
Aside from the neurologic and musculoskeletal features, numerous psychiatric and behavioral manifestations have been observed in association with Mobius syndrome (11); these include cataplexy (90), poor impulse control (33), sleep disturbances (05), and self-inflicted oral trauma (32). The prevalence of mental retardation is not notably increased relative to the clinically normal population (97), and the association with concurrent autism spectrum disorders does not appear as frequently as previously believed (13; 41). An investigation into the self-perception of children and adolescents with Mobius syndrome reported overall less depression and impulsivity in the group under study, when compared to normative data (12). Thus, it must be emphasized that with Mobius syndrome, the inability to fully express emotion through facial animation can be stigmatizing; self-perception and actual mood and emotions may not necessarily correlate with the impressions of observers and caregivers. As such, careful evaluations must be made before rendering psychiatric diagnoses in these patients (12; 09).
Other diagnostic entities that have been described in association with Mobius syndrome have included Wilms tumor (101), anomalous pulmonary venous connection (84), cavernous malformation (63), and hypoplastic left heart syndrome in association with maternal influenza A infection (42). A case of Mobius syndrome presenting in association with splenogonadal fusion and intestinal intussusception has been described (16). Single cases of Mobius syndrome occurring in association with neurofibromatosis type 1 and Taussig-Bing anomaly have also been characterized (39; 76).
This is a static, nonprogressive condition; however, mild improvement with age has been reported.
Complications will depend on degree of involvement but commonly include corneal irritation or ulceration, speech difficulties, aspiration, and feeding problems, particularly in the neonatal period resulting in poor growth. Speech difficulties and lack of facial expression may lead to the false impression of cognitive delay. Inability to express emotion may lead to social isolation (86). Individuals with Mobius syndrome may present with salivary gland alterations, which may lead to a higher risk of dental caries (58).
The etiology of Mobius syndrome is multifactorial, implicating both genetic and environmental factors. Four genetic loci have been described: (1) the Mobius syndrome gene 1 on chromosome 13, (2) Mobius syndrome gene 2 on chromosome 3, (3) Mobius syndrome gene 3 on chromosome 10, and (4) Mobius syndrome gene 4 on chromosome 1 (92). Modes of inheritance have been postulated to range from autosomal recessive to autosomal dominant and X-linked. However, most cases have been sporadic (54; 92). Genetic studies have revealed various chromosomal abnormalities, mainly translocations, in association with Mobius syndrome (33; 44). BASP1, residing in human chromosome 5p15.1-p15.2, and TTPsig-BASP1 on chromosome 13q have been analyzed in 19 patients, with both being excluded as candidate genes (91). Reports have documented de novo mutations in PLXND1 and REV3L genes, representing unrelated pathways involved in hindbrain development, as causes of Mobius syndrome (88). A case of Mobius syndrome occurring with congenital fibrosis of extraocular muscles has also been described, in association with de novo mutation in the KIF21A gene encoding a kinesin motor protein (03).
With respect to environmental factors, cases that show brainstem injury are presumed to have been acquired in development and implicate destruction by ischemia or infections (87; 89; 100; 51; 78; 75; 04). Several etiologies have been suggested from animal studies and case reports. These include the following: uterine artery clamping, attempted abortions with curettage at 12-weeks’ gestation (50), an unknown amount of methaqualone at 11-weeks’ gestation (82), ergotamine ingestion in early pregnancy (80), hyperthermia in the first trimester (83; 29; 50); and maternal ingestion during the pregnancy of teratogenic agents such as thalidomide, alcohol, and cocaine (50; 43; 71). There have also been observations of Mobius syndrome following administration of misoprostol, a synthetic prostaglandin E1 analog that is being used in some countries as an abortifacient (77; 66; 10; 31). In fact, in utero exposure to misoprostol has also been associated with a case of Mobius syndrome with coexistent holoprosencephaly, a midline-patterning defect (70). These associations support the etiologic hypothesis that the brainstem injury in Mobius syndrome is due to vascular disruption with resultant ischemic changes during fetal development.
The pathogenesis of congenital facial diplegia is heterogeneous. Towfighi and colleagues divided the condition into 4 etiopathologic groups: (1) congenital hypoplasia of the cranial nerve nuclei, (2) primary peripheral nerve involvement, (3) necrosis of brainstem nuclei due to an anoxic-infectious cause, and (4) myopathies (89).
In cases with hypoplasia or aplasia of the cranial nerve nuclei, there is an absence or diminution in the number of neurons in the various nuclei (89). The remaining neurons may be small or normal in size. Other brainstem structures such as the inferior olive may also be affected. Assessments have demonstrated, however, that even in patients demonstrating radiographic evidence of brainstem hypoplasia, the traversing motor and sensory tracts through the brainstem and the associated peripheral nerves may still be electrophysiologically intact (93). Furthermore, recognizing the diverse pathogenetic spectrum of Mobius syndrome, studies have observed that this condition can be stratified into 2 neurophysiologic phenotypes: 1 with rhombencephalic maldevelopment with selective sparing of small-size motor units, and 1 likely related to an acquired injury during intrauterine life, giving rise to neurogenic remodeling of motor units (21).
Aplasia of the cranial nerve nuclei may result from loss of function of specific developmental genes. Mice with gene-targeted disruptions of the hoxb-2 locus demonstrated severe facial paralysis resulting from a failure to form the somatic motor component of the facial nerve (07). The mice also demonstrated sternal defects. At least a portion of this gene’s effect may have resulted from the alteration in function of 2 other hox genes, hoxb-1 and hoxb-4.
Cases with apparent foci of necrosis in the brainstem show a decrease in neurons in the affected nuclei and calcifications or evidence of hemorrhage (87; 89; 100; 51; 93c). These lesions are presumed acquired during fetal development and reflect ischemia of brainstem structures (25). This is supported by the observation that watershed (boundary zone) infarcts in the fetal and neonatal brainstem, as confirmed and dated by postmortem examination, can clinically express as multiple cranial neuropathies, failure of central respiratory drive, or apnea, as well as Mobius syndrome and the Pierre Robin sequence (75). Additional support is similarly seen in associated anomalies such as the Poland anomaly and limb malformations, which are also presumed to have a vascular basis. The spectrum of clinical manifestations suggests multiple possible types and foci of injury during embryogenesis (20).
Peripheral neuropathy and myopathy are much less common manifestations and usually reflect more of an underlying generalized disorder involving either nerve or muscle. Included in this group is a disorder that has been reported as Mobius syndrome with peripheral neuropathy and hypogonadotrophic hypogonadism (64; 01). However, this represents a distinct entity and should be separated from Mobius syndrome.
Acquired facial palsy from delivery may present bilaterally, but the distribution of the weakness and lack of other associated palsies usually allow differentiation. The cardiofacial syndrome with asymmetric crying facies, congenital heart defects, and other anomalies may be confused with Mobius syndrome. Other neuromuscular disorders including infantile spinal muscular atrophy, congenital forms of myasthenia gravis, myotonic dystrophy, facioscapulohumeral dystrophy, and other myopathies may present initially with facial weakness in the newborn period (98).
The oromandibular-limb hypogenesis disorders overlap with Mobius syndrome. All members of this group, including hypoglossia-hypodactylia, Hanhart syndrome, glossopalatine ankylosis, and Charlie M syndrome, have a variety of limb and craniofacial anomalies (28).
As a syndrome with a heterogeneous spectrum of clinical manifestations and overlap, Mobius syndrome demonstrates marked similarities to the Athabascan brainstem dysgenesis syndrome, a disorder characterized clinically by horizontal gaze palsy, sensorineural deafness, central hypoventilation, and developmental delay. Key features distinguishing this syndrome from Mobius syndrome are essentially the pattern of CNS findings, specifically sensorineural deafness and central hypoventilation (36).
As a relatively rare congenital disorder, Mobius syndrome is relatively unknown and perhaps unrecognized among health care professionals (15). Early recognition is key as it can facilitate early diagnosis and treatment. Generally, diagnostic testing to evaluate the level of the lesion is indicated. Because of the variable pathogenesis, there is no single specific diagnostic modality for Mobius syndrome. EMG nerve conduction velocity should be performed to evaluate for other conditions in the differential diagnosis and to elucidate the level of the lesion. Results of such electrophysiological testing have previously demonstrated a spectrum of disturbance varying in degree of severity as well as neuroanatomic localization (94). Although head MRI and CT imaging are usually remarkable only for medial deviation of the eyes, other findings may include hypoplastic or dysplastic brainstem and bilateral symmetric calcifications adjacent to the fourth ventricle floor at the level of the sixth cranial nerve nuclei (48; 67). Absence of the abducens and facial nerves in MRI may be correlated with facial palsy and abduction limitations (45). In a reported case series, imaging has also revealed absence of the facial nerve (95). Additionally, there has been a reported case in which the middle cerebellar peduncles were absent (65). Ophthalmological examination should be performed to evaluate the strabismus and to assist in management (60; 06).
Audiologic functions in children and adolescents have been investigated (30). Findings demonstrated that there is generally no audiologic pattern for the hearing loss (conductive and/or neural sensory) observed in occasional patients. It appeared that the majority of the patients in the study presented with hearing in the normal range.
Overall, the primary principle modality for diagnostic assessment and stratification of Mobius syndrome is electrophysiologic testing (93; 21).
Management should be aimed at optimizing function and enhancing recovery by means of surgical correction and rehabilitation wherever possible. This includes correction of strabismus, speech-language therapy, and appropriate therapy and rehabilitation of any limb anomalies (69; 06). Studies have documented the benefits of early dental management with orthodontic appliances, reporting improvement in palate expansion and decreased severity of micrognathia following 24 months of treatment and follow-up (56). Severe skeletal open bite deformities can be treated with combined orthodontic and orthognathic surgery (18).
There have been several reconstructive procedures described for the management of the lack of facial animation, with some degree of success. To address facial paralysis, functional free muscle auto transplantation (transfer) is the generally accepted standard treatment principle (22). Such surgical interventions are usually multistage procedures and involve dynamic reconstruction with nerve grafting, followed by muscle autotransplantation. The timing of these procedures may play a significant role in outcome (08). Chuang and colleagues reported an alternate surgical treatment algorithm that involves a 1-stage procedure using spinal accessory nerve (CN XI)-innervated free muscle (22; 52). Butler and colleagues observed that patients with syndromic congenital facial palsies are more likely to have absent facial veins and facial artery agenesis compared to those with isolated congenital facial palsy, thus emphasizing the importance of preoperative planning for facial reanimation with free functional muscle transfer (17).
Cumulative experiences have been described, with characterization of generally positive long-term outcomes. Bilateral medial rectus recession has been effective in addressing esotropia with long-term stability (53). Segmental gracilis muscle transfer has given rise to long-lasting improvements in facial animation (23; 72). Experience from a large case series has also demonstrated the feasibility of gracilis muscle transfer, emphasizing the importance of donor nerve selection (Cardenas-Mejia and Palafox 2017).
The significance of postoperative physiotherapy has been emphasized, illustrating the phenomenon of brain plasticity (57). A case series describes the effects of direct tongue neurotization on speech intelligibility, reporting favorable results (85). Specific therapy and goals should be individualized (103; 86).
Polyhydramnios secondary to impaired swallowing may complicate a pregnancy with an affected fetus (82; 78). The limb abnormality may be detected on ultrasound (14). In a retrospective review of a prenatal ultrasound of a child with Mobius syndrome, Yoon and colleagues were able to see hyperechoic signals in the brainstem consistent with calcifications (102).
Mobius syndrome continues to be observed in association with maternal misoprostol administration during pregnancy. Additionally, patients whose mothers had taken misoprostol are more likely to develop bilateral palsy (31).
A patient with Mobius syndrome may present several anesthetic problems including weak swallow, difficulty in maintaining secretions, and a history of aspiration resulting in chronic pulmonary changes. Use of antisialagogues—atropine, scopolamine, or glycopyrrolate—is recommended.
Malignant hyperthermia has been reported in an infant with Mobius syndrome undergoing surgery (26). This occurred following exposure to sevoflurane and succinylcholine, which was reversed with dantrolene maintained for 24 hours. However, 10 hours following dantrolene discontinuation, there was recrudescence of malignant hyperthermia, which did not respond satisfactorily to treatment, leading to death.
Patients with Mobius syndrome should continue to receive intensive respiratory support postoperatively. As the principle anesthetic concern centers on the propensity of patients with Mobius syndrome encountering postoperative respiratory failure, consideration should be given to leaving the endotracheal tube in place to facilitate pulmonary care until it is certain that the patient is capable of handling secretions (47; 27). Overall, however, there do not seem to be contraindications to perform procedures, including bronchoscopy, in an outpatient setting (35).
Brian H Le MD
Dr. Le of Novant Health System has no relevant financial relationships to disclose.See Profile
Harvey B Sarnat MD FRCPC MS
Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.See Profile
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