AUTHOR AND EDITOR INFORMATION

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• Introduction
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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Möbius syndrome is due, in part, to loss of function of motor cranial nerves (CNs). Although von Graefe described a case of congenital facial diplegia in 1880, the syndrome was reviewed and defined further by Paul Julius Möbius, a German neurologist, in 1888 and 1892. Because of these contributions, Möbius is now the eponym used to describe the syndrome.  

The definition and diagnostic criteria for Möbius syndrome vary among authors. Both von Graefe and Möbius accepted only cases with both congenital facial diplegia and bilateral abducens nerve palsies as constituting Möbius syndrome. In 1939, Henderson broadened the definition and included cases with congenital unilateral facial palsy.

Other authors are more restrictive in attempts to eliminate conditions of a different pathogenesis being labeled as Möbius syndrome. These investigators require the presence of a congenital musculoskeletal anomaly in order to make the diagnosis. In most studies, Möbius syndrome is defined as congenital facial weakness combined with abnormal ocular abduction.

Pathophysiology

The complete pathophysiological description of Möbius syndrome remains elusive. Whether nerve, brainstem, or muscle aplasia is the primary event has not been established. Nerves that may be involved include CNs VI through XII, with general sparing of CN VIII. CN III and CN IV can be involved, but only rarely. The facial nerves (CN VII) are involved in all cases, the abducens nerves (CN VI) in a high percentage of cases (75%), and the hypoglossal nerves (CN XII) in only a minority of cases.

Numerous theories exist concerning the primary underlying pathogenesis. Möbius believed that the condition was degenerative or toxic in origin and that it involved the nuclei of the affected nerves. Some authors suggest that the underlying problem is an inherited congenital hypoplasia or agenesis of the CN nuclei. Approximately 2% of cases appear to have a genetic basis. In addition, theories of vascular etiologies of the syndrome have many proponents. One such theory involves disruption of flow in the basilar artery or premature regression of the primitive trigeminal arteries. A second vascular theory is a disruption of the subclavian artery supply that involves interruption of the embryonic blood supply. Still others view Möbius syndrome as a mesodermal dysplasia involving musculature derived from the first and second branchial arches. This theory holds that brainstem changes are secondary to retrograde atrophy of the CNs.

Simultaneous limb malformations with CN dysfunction suggests a disruption of normal morphogenesis during a critical period in the development of the embryonic structures of these regions, most likely at 4-7 weeks of gestation.

Frequency

United States

Möbius syndrome is a rare disorder. Only approximately 300 cases have been described in the English-language literature. The prevalence in the United States is reported as 0.002-0.0002% of births, or 1 case per 50,000 newborns.

International

In a nationwide Dutch survey reported in 2003, the prevalence of Möbius syndrome was at least 0.002% of births (4 cases per 189,000 newborns) for the years 1996-1998.

Mortality/Morbidity

Feeding problems at birth and in infancy may be severe and often are aggravated by associated micrognathia. In severe cases, death may occur in the perinatal period, often as a result of respiratory or bulbar problems. Life expectancy may be normal in patients with less extensive brainstem involvement.

• In a series from the Hospital for Sick Children in London, England, 8 of 29 patients died over the course of 18 years. All deaths occurred shortly after birth. Four of the deaths were due to respiratory or bulbar problems.
• Another striking feature causing morbidity in persons with Möbius syndrome is the high incidence of associated congenital deformities. The most common deformity is clubfoot. Brachial deformities and pectoral muscle hypoplasia have been described.
• A congenital condition called the Poland sequence, characterized by partial or complete absence of the pectoralis muscles and breast and ipsilateral hand malformations, is concurrent with Möbius syndrome in approximately 15% of patients.

Race

No racial predilection is described.

Sex

Most reported cases have been sporadic, with both sexes equally affected.

Age

Möbius syndrome is congenital, and most cases are diagnosed during infancy. The disease is not progressive, and the patient's presentation is generally based on the severity of the symptoms.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
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History

Because of the early age at which the syndrome becomes obvious, parents or other caretakers generally bring infant patients to medical attention. Facial and ocular symptoms are usually the presenting problems.

• Facial diplegia is the most noticeable symptom. This may be observed soon after birth with incomplete eyelid closure during sleep, drooling, and difficulty sucking.
• • On occasion, the facial paralysis is not noticed for a few weeks or months until the infant's inability to smile or the lack of facial movement with crying arouses the parents' concern.
• • Because of the facial and forehead immobility, the skin appears devoid of wrinkles.
• • In some cases, only a slight diminution in the width of the palpebral fissures during sleep may be noted.
• • Inability to close the mouth is the rule.
• • Undue prominence of the upper lip is a striking feature. In adults, the lower lip is usually everted and prominent.
• • Speech problems are reported in 76-90% of patients with Möbius syndrome. Speech is usually indistinct because of the patient's inability to close his or her lips and make labial sounds. In some cases, speech impairment may be severe.
• • Food is apt to lodge in the cheeks when the patient eats.
• The association of Möbius syndrome with anosmia and hypogonadotrophic hypogonadism (Kallmann syndrome) or with hypogonadism alone has been reported.
• The syndrome has been associated with autistic behavior. In 1989, Gillberg and Steffenburg¹ reported that autistic symptoms are present in 30-40% of children and young adults with Möbius syndrome. This has been confirmed in other series.
• Intelligence is usually normal, but mild mental retardation is thought to occur in approximately 10-15% of patients. Many authors report that without formal testing, intelligence may be underestimated because of the facial appearance.
• In a 2003 study involving extensive neuropsychological testing, Verzijl et al² found no diminishment in intellect, attention span, or memory in 12 adults with Möbius syndrome but not autism compared with the healthy population. However, these results cannot be extrapolated to patients with autism because they were not included in this study.
• In 1979, Towfighi et al proposed a classification based on pathologic differences observed in studies of patients with Möbius syndrome. The 4 proposed groups have no significant clinical correlations; however, they are as follows:³
• • Group I - Simple hypoplasia or atrophy of CN nuclei
  • Group II - Primary lesions in peripheral CNs
  • Group III - Focal necrosis in brain stem nuclei
  • Group IV - Primary myopathy with no CNS or CN lesions

Physical

Physical findings entirely depend on the case definition of Möbius syndrome.

• By using the most commonly accepted definition, the typical phenotypic appearance is an immobile facial appearance with various gaze palsies. Facial nerve palsy is usually bilateral and incomplete, involving either the upper or the lower portion of the face.
• • The resulting masklike face makes this diagnosis obvious upon initial inspection.
  • The flattened facial expression causes patients to have difficulties in relating to others because of their inability to convey emotions.
• External ocular palsies, including ptosis, accompany the facial diplegia in approximately 80% of patients. These extraocular abnormalities may be single or multiple.
• • Abducens nerve palsies are reported in approximately 75% of patients and are some of the most characteristic features of the syndrome.
  • • Most are bilateral and usually complete.
    • Abducens paralysis is the only ocular palsy in approximately 50% of patients.
    • Affected children may be born with marked internal strabismus.
    • Ophthalmoplegia may be partial or complete.
    • Lateral gaze paralysis, which indicates medial longitudinal fascicular involvement, is often present.
  • Secondary to the feebleness of blinking and the incomplete closure of the eyelids during sleep, the cornea and conjunctiva are poorly protected. Recurrent or chronic conjunctivitis frequently occurs. Corneal opacities are unusual but sometimes observed in adults.
• Bulbar weakness may be mild or severe. Dysphagia, caused by paresis of CNs IX and X, is common.
• The hypoglossal nerve is the third most commonly affected CN and is involved in approximately 25% of reported cases. Involvement of the hypoglossal nerves often leads to atrophy of the tongue. Patients may be unable to protrude their tongue beyond their lips because of this weakness.
• • This involvement may result in paralysis and hypoplasia of the tongue, or fasciculations may be seen as a result of hypoglossal denervation.
  • The ocular muscles are always involved when the tongue is affected.
• Masticatory muscles are rarely affected. Instances of bilateral paresis of the soft palate and scattered instances of dysphagia (some of which resolve in infancy) have been reported. Infantile nasal regurgitation has been described in the literature.
• Musculoskeletal abnormalities occur in one third or more of patients with Möbius syndrome. These anomalies may include talipes equinovarus, brachydactyly, syndactyly, congenital amputations (see Media File 1), arthrogryposis, smallness of limbs, and occasionally hypoplasia or absence of the pectoralis major muscles (Poland anomaly).
• • The Poland anomaly is generally unilateral and is associated with mammary hypoplasia of the same side.
  • An estimated 15% of patients with Möbius syndrome have missing truncal muscle groups, including the pectoralis or trapezius muscles. Other muscle groups that may be aplastic or hypoplastic include the latissimus dorsi, external abdominal muscles, serratus anterior, and intercostal muscles.
  • Brachial malformation is common.
  • • It occasionally involves the arm, whereas the hand is always affected.
    • Reports include congenital amputation of the hand and clubhand. In some cases, the affected hand is smaller than the other hand.
    • Syndactyly is not uncommon, and brachydactyly is frequently reported. Other abnormalities in the upper extremities include finger webbing and an absence or hypoplasia of the radius, ulna, metacarpal, or phalanx.
  • Clubfoot, frequently bilateral, occurs in almost one third of patients. The deformity is usually correctable with surgery.
• Numerous orofacial abnormalities are also present.
• • In several cases, the root of the nose has been described as broad and rather flat. 
  • Bilateral epicanthus has been reported, and scattered instances of ear deformities have been described (usually bilateral and confined to the lobe). 
  • An arched palate and bifid uvula have been described, as have microglossia, microstomia, micrognathia, teeth and jaw malformations, and hypertelorism.
• Other less common anomalies are dextrocardia, arthrogryposis multiplex congenita, and the Klippel-Feil anomaly.
• Skin abnormalities have been associated with the Möbius syndrome, including café-au-lait pigmentation, webbing of the axilla, and an absence of subcutaneous tissue.

Causes

The pathogenesis and etiology of Möbius syndrome appear to be multifactorial and remain controversial. Most investigators agree that in a subset of patients, the condition is predetermined genetically; however, most cases are sporadic. Etiologic hypotheses include hypoxic/ischemic injury and intrauterine toxic exposure.

• The syndrome is listed as Online Mendelian Inheritance in Man (OMIM) Number 15700⁴, with a gene map locus of 13q12.2-q13. Scattered reports have described specific genetic localizations in Möbius syndrome. More reports will appear as the field of molecular biology expands. Genetic mapping, when available, will help in further defining the syndrome.
• • In 1977, Ziter et al⁵ reported a variant of Möbius syndrome co-segregating with a reciprocal translocation between chromosomes 1 and 13, ie, t(1p34;13q13), in at least 7 members of an affected family over 3 generations. In 1991, Slee et al⁶ described a 2.5-year-old girl with Möbius syndrome who had a deletion of band q12.2 on chromosome 13. The child's mother's karyotype was normal, but paternal chromosome studies were unavailable. (Her father had died.) Both reports suggested that a gene responsible for Möbius syndrome is located in region 13q12.2-q13.
  • In 1996, Kremer et al⁷ described a large pedigree with autosomal dominant Möbius syndrome consisting largely of asymmetric bilateral facial paresis. After exclusion of the candidate region on 13q12.2-13, they localized a gene to 3q21-22, raising the possibility of genetic heterogeneity of the syndrome.
  • In 1997, Nishikawa et al⁸ reported a boy with a Möbiuslike syndrome (ie, facial diplegia and ptosis but with normal extraocular movements and no skeletal anomalies) with a reciprocal translocation between chromosomes 1 and 2 (p22.3, q21.1).
• Familial cases are reported.
• • In one family, affected siblings had facial diplegia, deafness, and mental retardation but no skeletal abnormalities.
  • In another series from 2 kindreds, more than one affected sibling had Möbius syndrome, but the nonconsanguineous parents were neurologically healthy.
  • A dominantly inherited syndrome (with the clinical features of Möbius syndrome and clubfoot, digital abnormalities, and arthrogryposis) was described in a family with 15 affected members in 2 generations.
• Because of inconsistency in defining the condition, the role of inheritance in Möbius syndrome remains unclear.
• • Pedigrees with autosomal dominant, autosomal recessive, and X-linked recessive inheritance patterns have been described. For this reason, providing genetic counseling to parents with an affected child remains difficult.
• • In facial diplegia without eye muscle involvement, the hereditary predisposition is greater, but recurrence depends on eliminating the known, genetically determined primary muscle or anterior horn cell disorders.
• • Baraitser⁹ stated that when the definition of the Möbius syndrome is restricted to the presence of CN VI and VII palsies (with or without bulbar involvement but with primary skeletal malformations), the risk to offspring of having the disease is low (2%).
• In addition to genetic predisposition and vascular interruption hypotheses, evidence suggests a toxic origin of Möbius syndrome in some cases.
• • In a 1998 study of Brazilian infants, Pastuszak et al¹⁰ found a strong association between Möbius syndrome and prenatal use of misoprostol, a synthetic prostaglandin analog used to treat upper gastrointestinal ulceration.
• • Misoprostol was self-administered by the mothers in Brazil as an abortifacient. Misoprostol is thought to cause an ischemic event in the embryonic brain stem early in gestation.
• • Ergotamine exposure during early fetal development has been implicated in several cases of Möbius syndrome because of its vasoconstrictive properties.
• • In a 2005 case report, Puvabanditsin et al¹¹ described an infant with Möbius syndrome associated with Poland anomaly that may have been related to ongoing maternal cocaine use during the first trimester of the pregnancy. The authors suggested that the cocaine exposure may have disrupted the fetal vascular supply.
• By definition, traumatic injuries are not part of the Möbius syndrome.

DIFFERENTIALS

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Other Problems to be Considered

Abducens (CN VI) nerve palsy
Brainstem syndromes
Duane syndrome
Kallmann syndrome
Metabolic neuropathy
Myotonic diseases
Neuromuscular diseases
Poland anomaly
Klippel-Feil anomaly

WORKUP

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Lab Studies

• No diagnostic laboratory studies yield findings specific to Möbius syndrome.

Imaging Studies

• Some physicians do not pursue imaging studies of the brain, but many experts recommend them.
• • CT scanning or MRI of the brain may demonstrate bilateral calcifications in the regions of the CN VI nuclei.
  • The brainstem may appear hypoplastic with straightening of the fourth ventricular floor.
  • One report describes bilateral calcifications of the basal ganglia on the brain CT scans of 2 siblings with classic Möbius syndrome. These calcifications are not specific for the disease.
  • Brain MRI may help in determining whether other, perhaps genetically determined, cerebral malformations are present.
  • Although not usually indicated, prenatal ultrasonography has depicted basal ganglial and brainstem calcifications in the brains of developing infants.

Other Tests

• Electromyography
• • Some instances of facial palsy occur with birth trauma, especially with the use of forceps in breech deliveries. By definition, traumatic injuries are not part of Möbius syndrome. Timing of the injury to the facial nerve may be important, and electromyography (EMG) can assist in this regard.
  • Denervation potentials are present only if the facial nuclei or nerves were injured 2-3 weeks (or more) before the study. Facial muscles that are congenitally aplastic or hypoplastic as a result of Möbius syndrome or nerve injury occurring early in gestation do not demonstrate active denervation. This finding can help in differentiating Möbius syndrome from perinatal trauma to peripheral nerves.
  • In 2006, Cattaneo et al¹² reported on a study of 24 Möbius syndrome patients after neurophysiologic testing including EMG and found 2 different defined phenotypes. Based on their EMG data, the authors postulated that the first group had rhombencephalic maldevelopment, while the second group seemed to have acquired a nervous system injury during intrauterine life.
  • In a 1996 study of EMG results from 7 patients with Möbius syndrome, Jaradeh et al¹³ suggested the primary cause of neural involvement was prenatal brainstem damage involving the motor nuclei and their internuclear connections.
  • The diagnosis of Möbius syndrome soon after birth may be difficult. Möbius syndrome can easily be confused with congenital myopathies or muscular dystrophies or congenital myotonic dystrophy. If abnormal, EMG findings can help in the differential diagnosis.

Histologic Findings

Few published cases contain pathologic descriptions.

Gross findings include asymmetry of the medulla, but the external appearance of the brain generally is normal.

Upon histologic evaluation, the most notable abnormalities have been seen in the motor nuclei of the CNs, especially in CN VI (see Media File 2), CN VII, and CN XII and, to a lesser extent, in CN III and CN XI nuclei. CN VI often shows the most striking changes, with near-total neuronal loss and, sometimes, necrosis (see Media Files 3-4). The necrotic foci are round, well circumscribed, and basophilic. Degenerative periodic acid-Schiff–positive material may be seen. The necrotic foci may be surrounded by radiating cell processes.

Gliosis may be seen in the affected regions. Occasional axonal spheroids have been seen in the periphery of the necrotic lesions. The pyramids may appear underdeveloped. Atrophy of the facial muscles has been described, with adipose and fibrous tissue replacement.

TREATMENT

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Medical Care

Möbius syndrome is congenital and nonprogressive. However, no definitive treatment is available. To date, medical care is supportive and symptomatic.

• Treatment for corneal ulcerations or abrasions may be required. This is secondary to exposure keratitis and conjunctivitis secondary to incomplete eyelid closure.
• Congenital limb amputations or other musculoskeletal abnormalities may significantly compromise patients with Möbius syndrome. Splints, prostheses, or even prophylaxis for deep venous thrombosis may be indicated.
• For a number of reasons, patients may be predisposed to infections.
• • Brainstem abnormalities may predispose patients to aspiration pneumonia, which may be complicated by pulmonary infections. Vigilance and a low threshold for treatment are required.
  • If the patient has structural anomalies of the ear, otitis media may complicate the patient's clinical course and require intervention.
• Research into the psychological family dynamics of Möbius syndrome patients has drawn attention to the problems of parental bonding and possible disturbances of family care. This can occur because of a lack of feedback to the mother from the child, who may not be able to signal to her in the normal fashion by smiling or visual following.
• When affected children reach an age of self-awareness, they realize that others notice the facial immobility. Facial mobility may increase with age. By school age, the condition may be less socially embarrassing than before. Family or individual counseling might prove helpful in these situations.
• Neuropsychological and intelligence testing are helpful in predicting and assisting possible learning deficiencies, autism, or various visual apraxias.

Surgical Care

Surgical care is symptomatic or cosmetic but not curative of the underlying syndrome.

• Clubfoot, frequently bilateral, occurs in almost one third of patients. In most, the deformity can be corrected partially or entirely by means of orthopedic procedures.
• Airway functions commonly are compromised. Tracheotomy may be required to support the airway and permit tracheobronchial clearing.
• With the diffuse incidence of feeding problems in children with Möbius syndrome, supplemental energy intake via a feeding gastrostomy tube may be required. Nissen fundoplication procedures have not been helpful in treating neurogenic dysphagia and associated aspiration.
• Most ophthalmologists recommend delaying surgery for strabismus because the condition frequently improves with age. Ocular surgical procedures have been successful in some patients with Möbius syndrome. In older patients, insertion of a gold weight into the eyelid may allow lid closure to protect the cornea.
• Reanimation procedures to counteract the facial nerve paralysis may be successful. Restoration of function may be more successful if surgery is performed before age 7 years.
• • Otolaryngologists and plastic surgeons have used the unaffected accessory nerve or the mesenteric branch of CN V as donors for reinnervation procedures.
• • Other surgeons have designed living devices, composed of muscle and tendon transplants combined with reinnervation procedures, that have restored at least partial control of the facial musculature.

Consultations

• Associated deficiencies in Möbius syndrome and its variants require a multidisciplinary approach by skilled specialists.
• Consultations may be required from pediatricians, general surgeons, pediatric dentists, orthopedic surgeons, ophthalmologists, pediatric otolaryngologists, psychologists, physiatrists, occupational and physical therapists, audiologists, and speech therapists.

Diet

If the brainstem is affected severely (enough to cause dysphagia), a dietician might assist with aspiration prevention.

Activity

Activity is not specifically limited in patients with Möbius syndrome, but it may be limited by the patient's physical abilities.

MEDICATION

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With few exceptions, pharmacologic intervention is used only for symptomatic treatment.

Drug Category: Antibiotics

Proper antibiotic therapy should be started in the event of infections such as pneumonia or otitis media.

FOLLOW-UP

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Further Outpatient Care

• Physical therapy might be useful for managing congenital orthopedic problems or for postoperative care if orthopedic intervention is required.
• Occupational therapy may help patients, especially those without hands or digits, accomplish activities of daily living.
• Speech therapy may be started if the deficits of lower CNs are severe. Severe facial nerve paralysis often mechanically affects speech.

Complications

• Complications depend on the severity of the patient’s deficits. They may include aspiration pneumonia, corneal ulceration/abrasion, dysphagia, and poor nutrition.

Prognosis

• Möbius syndrome is a static neurologic defect.
• • In patients with severe brainstem compromise that causes dysphagia, aspiration, and an inability to protect the airway, death may occur at a young age.
  • In its mildest form, Möbius syndrome is not lethal.

Patient Education

• Parental education is required early in the child's life. Discuss airway compromise and the possible need for tracheotomy (if the condition is severe).
• Parents and patients also may require education concerning appliances that enable ambulation, if applicable.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Because birth trauma can cause a syndrome with a presentation similar to that of Möbius syndrome, birth trauma should be excluded as soon as possible after birth.

MULTIMEDIA

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Media file 1:  Autopsy photograph of a 3-month-old child with Möbius syndrome who died unexpectedly demonstrates congenital amputation of the left hand at the wrist.
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Media file 2:  Low-power photomicrograph of a brainstem specimen in an infant with Möbius syndrome who died at age 3 months. Image shows bilateral lesions in the pons of the abducens nuclei (hematoxylin and eosin stain).
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Media type:  Photo

Media file 3:  Medium-power photomicrograph from the abducens nucleus in an infant with Möbius syndrome who died demonstrates diffuse necrosis and neuronal loss (hematoxylin and eosin stain).
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Media type:  Photo

Media file 4:  High-power photomicrograph shows a lesion of an abducens nerve nucleus in an infant with Möbius syndrome who died at age 3 months. Image shows neuronal loss, necrosis, myxoid change, and a circumferential rim of thickened glial fibrils (hematoxylin and eosin stain).
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Media type:  Photo

REFERENCES

Section 11 of 11

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Article Last Updated: Apr 30, 2007