eMedicine Specialties > Neurology > Pediatric Neurology

Mobius Syndrome

Author: Cheryl Ann Palmer, MD, Professor, Departments of Pathology and Neurology, University of Alabama at Birmingham School of Medicine; Consulting Staff, Departments of Pathology and Neurology, University of Alabama at Birmingham Hospital; Consulting Staff, Departments of Pathology and Neurology, Veteran Affairs Medical Center; Consulting Staff, Department of Pathology, Children's Hospital of Alabama
Contributor Information and Disclosures

Updated: Mar 17, 2009

Introduction

Background

Möbius syndrome is due, in part, to loss of function of motor cranial nerves. Although von Graefe described a case of congenital facial diplegia in 1880¹ , the syndrome was reviewed and defined further by Paul Julius Möbius, a German neurologist, in 1888² and 1892³ . 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.⁴

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 cranial nerves (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.^2,3 Some authors suggest that the underlying problem is an inherited congenital hypoplasia or agenesis of the cranial nerve nuclei. Approximately 2% of cases appear to have a genetic basis.⁵ 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 cranial nerves.

Simultaneous limb malformations with cranial nerve 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 1996-1998⁵ .

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 problems⁶ .
• 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

Both sexes are equally affected⁷ .

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

History

Because of the early age at which Möbius 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.⁸
  • 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.⁹
• 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 al found no diminishment in intellect, attention span, or memory in 12 adults with Möbius syndrome but not autism compared with the healthy population.¹⁰ However, these results cannot be extrapolated to patients with autism because they were not included in this study.
• Möbius syndrome has been associated with autistic behavior. In 1989, Gillberg and Steffenburg reported that autistic symptoms are present in 30-40% of children and young adults with Möbius syndrome.¹¹ This has been confirmed in other series.
• In 1979, Towfighi et al proposed a classification based on pathologic differences observed in studies of patients with Möbius syndrome.¹² The 4 proposed groups have no significant clinical correlations; however, they are as follows:
  • Group I - Simple hypoplasia or atrophy of cranial nerve nuclei
  • Group II - Primary lesions in peripheral cranial nerves
  • Group III - Focal necrosis in brain stem nuclei
  • Group IV - Primary myopathy with no CNS or cranial nerve 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 cranial nerve and is involved in approximately 25% of reported cases.⁸ 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.
• A case of Möbius syndrome presenting with congenital bilateral vocal cord paralysis was reported by Kanemoto in 2007.¹³
• 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.
• In a 2007 study, the majority of 17 patients with Möbius syndrome had hearing in the normal range, with no consistent abnormal pattern present in the remaining patients.¹⁴
• 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).
  
  

  

  Autopsy photograph of a 3-month-old child with Möbius syndrome who died unexpectedly demonstrates congenital amputation of the left hand at the wrist.

  [ CLOSE WINDOW ]

  

  Autopsy photograph of a 3-month-old child with Möbius syndrome who died unexpectedly demonstrates congenital amputation of the left hand at the wrist.

  
  
  • The Poland anomaly, first associated with Möbius syndrome in 1973¹⁵ , 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 15700¹⁶ , 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 al 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.¹⁷ In 1991, Slee et al described a 2.5-year-old girl with Möbius syndrome who had a deletion of band q12.2 on chromosome 13.¹⁸ 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 al 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.¹⁹
• In 1997, Nishikawa et al reported a boy with a Möbius-like 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).²⁰
• 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.
• Baraitser 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%).⁶
• 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 al found a strong association between Möbius syndrome and prenatal use of misoprostol, a synthetic prostaglandin analog used to treat upper gastrointestinal ulceration.²¹
• 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 al 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.²²
• The mother of the infant with Möbius syndrome reported by Kanemoto in 2007 was also treated with zonisamide during pregnancy for prepartum epilepsy.  Since the teratogenicity of zonisamide has not been clearly defined, the authors were unable to exclude prenatal exposure of zonisamide as a possible cause of Möbius syndrome.¹³
• By definition, traumatic injuries are not part of the Möbius syndrome.

• Search for CME/CE on This Topic »

• Arthrogryposis (Pediatrics: Genetics and Metabolic Disease)
• Congenital Facial Paralysis (Otolaryngology and Facial Plastic Surgery)
• Chest Wall Deformities (Pediatrics: Cardiac Disease and Critical Care Medicine)
• Birth Trauma (Pediatrics: Cardiac Disease and Critical Care Medicine)