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Mobius Syndrome

  • Author: Cheryl Ann Palmer, MD; Chief Editor: Amy Kao, MD  more...
 
Updated: Aug 09, 2016
 

Background

In most studies, Möbius syndrome is defined as congenital facial weakness combined with abnormal ocular abduction. Möbius syndrome is due, in part, to the loss of function of motor cranial nerves (CNs). Most cases are diagnosed during infancy. The disease is not progressive. (See Etiology, Prognosis, Presentation, and Workup.)

Although von Graefe described a case of congenital facial diplegia in 1880,[1] the syndrome was reviewed and defined further by Paul Julius Möbius, a German neurologist, in 1888[2] and 1892.[3] 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. Von Graefe and Möbius accepted only cases with 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. (See Presentation and Workup.)[4]

Other authors are more restrictive in their definition, as a means of preventing the term Möbius syndrome from being assigned to conditions of a different pathogenesis. These investigators require the presence of a congenital musculoskeletal anomaly in order to make the diagnosis.

Congenital deformities

A striking feature 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 also been described. (See Presentation and Treatment.)

A congenital condition called the Poland sequence, characterized by ipsilateral hand malformations and by partial or complete absence of the pectoralis muscles and breast, is concurrent with Möbius syndrome in approximately 15% of patients.[5] (See Etiology and Presentation.)

Classification

In 1979, Towfighi et al proposed a classification system for Möbius syndrome based on pathologic differences observed in studies of patients with the syndrome.[6] The 4 proposed groups, which have no significant clinical correlations, are as follows:

  • Group I - Simple hypoplasia or atrophy of CN nuclei
  • Group II - Primary lesions in peripheral CNs
  • Group III - Focal necrosis in brainstem nuclei
  • Group IV - Primary myopathy with no central nervous system (CNS) or CN lesions
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Etiology

The etiology of Möbius syndrome remains controversial, but it appears to be multifactorial. Most investigators agree that in a subset of patients, the condition is predetermined genetically (approximately 2% of cases appear to have a genetic basis).[7] However, most cases are sporadic. Etiologic hypotheses include hypoxic/ischemic injury and intrauterine toxic exposure. By definition, traumatic injuries are not part of the Möbius syndrome.

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.

 

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Epidemiology

Mobius 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.[7] 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.[7] In 2007, the Möbius Syndrome Foundation estimated that 2000 individuals worldwide have the condition.[8]

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Prognosis

Möbius syndrome is a static neurologic defect. Complications of Möbius syndrome depend on the severity of the patient’s deficits. They can include poor nutrition, dysphagia, aspiration pneumonia, and corneal ulceration/abrasion. In its mildest form, Möbius syndrome is not lethal.

In patients with severe brainstem compromise that causes dysphagia, aspiration, and an inability to protect the airway, death may occur at a young age.

Ear deformities have been described in patients with Möbius syndrome. In such cases, otitis media may complicate the patient's clinical course and require intervention.

In patients with Möbius syndrome, 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 British study, 8 of 29 patients with Möbius syndrome died over the course of 18 years. All deaths occurred shortly after birth. Four of the deaths were due to respiratory or bulbar problems.[9]

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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.

The Moebius Syndrome Foundation states the following on its webpage: "The mission of the Möbius Syndrome Foundation is to provide information and support to individuals with Möbius syndrome and their families, promote greater awareness and understanding of Möbius syndrome, and to advocate for scientific research to advance the diagnosis and treatment of Möbius syndrome and its associated conditions." A great deal of useful information, as well as support group information, is available on the Web site.[10]

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Pathophysiology

Numerous theories exist concerning the primary underlying pathogenesis of Möbius syndrome. Möbius himself 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 CN nuclei.

Some 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.

The close relationship embryologically between the motor nuclei of the sixth and seventh CNs explains the pathology of this congenital condition.[11]

Simultaneous limb malformations with CN dysfunction suggest 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’ gestation.

From a clinical point of view, regardless of the site of malformation, the result is absence of a functional neuromuscular system in the affected regions.[11]

Vascular interruption

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.

Genetics

The syndrome is listed as Online Mendelian Inheritance in Man (OMIM) Number 15700,[12]  with a gene map locus of 13q12.2-q13. A study found no microdeletions in this critical region and excluded several candidate genes.[13]  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.[14]  In 1991, Slee et al described a girl aged 2.5 years with Möbius syndrome who had a deletion of band q12.2 on chromosome 13.[15]  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 asymmetrical, 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.[16]

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).[17]

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 1 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%).[9]

Toxins

In addition to genetic predisposition and vascular interruption hypotheses, evidence suggests a toxic origin for 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.[18]  Misoprostol was self-administered by the mothers in Brazil as an abortifacient. Misoprostol is thought to cause an ischemic event in the embryonic brainstem early in gestation.

Exposure to ergotamine, which has vasoconstrictive properties, during early fetal development has been implicated in several cases of Möbius syndrome.[19]

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.[20]

Kanemoto reported on the mother of an infant with Möbius syndrome who was 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 to zonisamide as a possible cause of Möbius syndrome.[21]

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Contributor Information and Disclosures
Author

Cheryl Ann Palmer, MD Professor of Pathology, Director of Neuropathology, Director of Pathology Residency Program, Department of Pathology, Huntsman Cancer Institute, University of Utah School of Medicine

Cheryl Ann Palmer, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuropathologists, Society for Neuro-Oncology, International Society of Neuropathology

Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD Attending Neurologist, Children's National Medical Center

Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, Child Neurology Society

Disclosure: Have stock from Cellectar Biosciences; have stock from Varian medical systems; have stock from Express Scripts.

Acknowledgements

Robert J Baumann, MD Professor of Neurology and Pediatrics, Department of Neurology, University of Kentucky College of Medicine

Robert J Baumann, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, and Child Neurology Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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