Clinical manifestations

Presentation and course

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. Reduced oral intake during the neonatal period may lead to early failure to thrive (67). 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 (73; 62).

The distribution of the facial palsy is often bilateral and incomplete (34; 36). 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; 45). Although the distribution of involvement is typically bilateral, two cases of ipsilateral unilateral palatal weakness have been described, with investigations failing to reveal a specific etiology (39). Ankyloglossia superior, a condition characterized by a connection between the tongue and hard palate, has been described in a patient with Mobius syndrome (27).

Limb and craniofacial abnormalities are frequent (56). Children with Mobius syndrome may have talipes equinovarus (45), 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 (79). Craniofacial features have included epicanthus, external ear anomalies, bifid uvula, cleft palate, micrognathia, and, rarely, other branchial muscle defects (24; 81). Global hypotonia, giving rise to symptoms suggestive of a severe infantile form of a congenital muscular disorder, may also be the presenting manifestation (37).

In addition to limb and craniofacial abnormalities, lower brainstem dysfunction in Mobius syndrome can give rise to an altered urodynamics, leading neurogenic bladder from which a patient may encounter increased susceptibility to urinary tract infections, hydronephrosis, and vesicoureteral reflux (78).

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 two distinct neurophysiologic phenotypes. In one 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 (22).

In addition, previously three specific patterns of alterations in ocular motility were described (21). 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 (69). 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 (52). 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 (12); these include cataplexy (86), 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 (93), and the association with concurrent autism spectrum disorders does not appear as frequently as previously believed (14; 40). 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 (13). 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 (13; 10).

Other diagnostic entities that have been described in association with Mobius syndrome have included Wilms tumor (95), anomalous pulmonary venous connection (77), cavernous malformation (59), and hypoplastic left heart syndrome in association with maternal influenza A infection (41). A case of Mobius syndrome presenting in association with splenogonadal fusion and intestinal intussusception has been described (17). Single cases of Mobius syndrome occurring in association with neurofibromatosis type 1 and Taussig-Bing anomaly have also been characterized (38; 72).

Prognosis and complications

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 (83). Individuals with Mobius syndrome may present with salivary gland alterations, which may lead to a higher risk of dental caries (55).

Biological basis

Etiology and pathogenesis

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 (88). Modes of inheritance have been postulated to range from autosomal recessive to autosomal dominant and X-linked. However, most cases have been sporadic (51; 88). Genetic studies have revealed various chromosomal abnormalities, mainly translocations, in association with Mobius syndrome (33; 42). 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 (87). Reports have documented de novo mutations in PLXND1 and REV3L genes, representing unrelated pathways involved in hindbrain development, as causes of Mobius syndrome (84). 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). A case of Poland-Mobius syndrome in association with a maternally inherited missense variant of the PLXND1 was reported (28).

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 (85; 48; 71; 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 (47), an unknown amount of methaqualone at 11-weeks’ gestation (76), ergotamine ingestion in early pregnancy (74), hyperthermia in the first trimester (47); and maternal ingestion during the pregnancy of teratogenic agents such as thalidomide, alcohol, and cocaine (47; 66). 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 (11; 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 (65). 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 four 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 (85).

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 (85). 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 (89). Furthermore, recognizing the diverse pathogenetic spectrum of Mobius syndrome, studies have observed that this condition can be stratified into two neurophysiologic phenotypes: one with rhombencephalic maldevelopment with selective sparing of small-size motor units, and one likely related to an acquired injury during intrauterine life, giving rise to neurogenic remodeling of motor units (22).

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 two 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 (85; 48; 89c). 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 (71). 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 (21).

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 (01). However, this represents a distinct entity and should be separated from Mobius syndrome.

Diagnostic workup

As a relatively rare congenital disorder, Mobius syndrome is relatively unknown and perhaps unrecognized among health care professionals (16). 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 (90; 46). 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 (63). Absence of the abducens and facial nerves in MRI may be correlated with facial palsy and abduction limitations (43). In a reported case series, imaging has also revealed absence of the facial nerve (91). Additionally, there has been a reported case in which the middle cerebellar peduncles were absent (61). Ophthalmological examination should be performed to evaluate the strabismus and to assist in management (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 (89; 22).

Management

Management should be aimed at optimizing function and enhancing recovery by means of surgical correction and rehabilitation wherever possible. Functional objectives include correction of strabismus, speech-language therapy, and appropriate therapy and rehabilitation of any limb anomalies (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 (53). Severe skeletal open bite deformities can be treated with combined orthodontic and orthognathic surgery (19).

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 (23). Gracilis neuromuscular transplant is considered the gold standard for facial animation in Mobius syndrome (09). 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 (23; 49). 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 (18).

The significance of postoperative physiotherapy has been emphasized, illustrating the phenomenon of brain plasticity (54). A case series describes the effects of direct tongue neurotization on speech intelligibility, reporting favorable results (82). Specific therapy and goals should be individualized (83).

Outcomes

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 (50). Segmental gracilis muscle transfer has given rise to long-lasting improvements in facial animation (68). Experience from a large case series has also demonstrated the feasibility of gracilis muscle transfer, emphasizing the importance of donor nerve selection (20). A retrospective examination of pediatric patients who had undergone facial animation surgery with at least five years of follow-up confirmed long-term stability of gracilis transplantation in surgical facial animation (09).

Special considerations

Pregnancy

Polyhydramnios secondary to impaired swallowing may complicate a pregnancy with an affected fetus (76). The limb abnormality may be detected on ultrasound (15). 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 (96).

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).

Anesthesia

Airway management in patients with Mobius syndrome can be difficult due to the presence of orofacial malformations (60). In a study involving 51 patients, Telich-Tarriba and colleagues reported that 38 patients were intubated in a single attempt whereas the remainder were successfully intubated on a second attempt (80).

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 there is higher risk of respiratory impairment and dysphagia, leading to aspiration pneumonia (60). 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 (29). Overall, however, there do not seem to be contraindications to perform procedures, including bronchoscopy, in an outpatient setting (35).